Antiviral pyrazolopyridine compounds

ABSTRACT

The present invention provides compounds of formula (I): 
                         
pharmaceutical compositions containing the same, processes for preparing the same and their use as pharmaceutical agents.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a 371 Application of PCT/US02/08793, filed 21 Mar.2002, which claims priority to U.S. application Ser. No. 60/282,749,filed 10 Apr. 2001.

BACKGROUND OF THE INVENTION

The present invention relates to novel compounds, pharmaceuticalformulations comprising these compounds, and the use of these compoundsin therapy. More particularly, the present invention relates tocompounds for the prophylaxis and treatment of herpes viral infections.

Of the DNA viruses, those of the herpes group are the sources of themost common viral illnesses in man. The group includes herpes simplexvirus types 1 and 2 (HSV1 and 2), varicella zoster virus (VZV),cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpes virus type6 (HHV-6), human herpes virus type 7 (HHV-7) and human herpes virus type8 (HHV-8). HSV-1 and HSV-2 are some of the most common infectious agentsof man. Most of these viruses are able to persist in the host's neuralcells; once infected, individuals are at risk of recurrent clinicalmanifestations of infection which can be both physically andpsychologically distressing.

Herpes simplex viruses (HSV-1 and -2) are the causative agents of herpeslabialis and genital herpes. HSV infection is often characterised byextensive and debilitating lesions of the skin, mouth and/or genitals.Primary infections may be subclinical although tend to be more severethan infections in individuals previously exposed to the virus. Ocularinfection by HSV can lead to keratitis or cataracts thereby endangeringthe host's sight. Infection in the new-born, in immunocompromisedpatients or penetration of the infection into the central nervous systemcan prove fatal. In the US alone, 40 million individuals are infectedwith HSV-2, a number that is expected to increase to 60 million by 2007.Over 80% of individuals infected with HSV-2 are unaware they carry andspread the virus, and of those diagnosed less than 20% received oraltherapies. The net result is that less than 5% of the infectedpopulation are treated. Likewise of the 530 million individualsworldwide who carry HSV-1, 81% of the symptomatic population remainuntreated. No cure exists for HSV infection, and once infected,individuals carry the virus for life in a dormant state. Reactivation ofthe virus from latency occurs periodically and may be triggered bystress, environmental factors, and/or suppression of the host immunesystem. Currently, the use of nucleoside analogs such as valaciclovir(Valtrex®) and aciclovir (Zovirax®) is the standard of care for managinggenital herpes virus outbreaks.

Varicella zoster virus (VZV) (also know as herpes zoster virus) is aherpes virus which causes chickenpox and shingles. Chickenpox is theprimary disease produced in a host without immunity, and in youngchildren is usually a mild illness characterised by a vesicular rash andfever. Shingles or zoster is the recurrent form of the disease whichoccurs in adults who were previously infected with VZV. The clinicalmanifestations of shingles are characterised by neuralgia and avesicular skin rash that is unilateral and dermatomal in distribution.Spread of inflammation may lead to paralysis or convulsions. Coma canoccur if the meninges become affected. VZV is of serious concern inpatients receiving immunosuppressive drugs for transplant purposes orfor treatment of malignant neoplasia and is a serious complication ofAIDS patients due to their impaired immune system.

In common with other herpes viruses, infection with CMV leads to alifelong association of virus and host. Congenital infection followinginfection of the mother during pregnancy may give rise to clinicaleffects such as death or gross disease (microcephaly,hepatosplenomegaly, jaundice, mental retardation), retinitis leading toblindness or, in less severe forms, failure to thrive, andsusceptibility to chest and ear infections. CMV infection in patientswho are immunocompromised for example as a result of malignancy,treatment with immunosuppressive drugs following transplantation orinfection with Human Immunodeficiency Virus, may give rise to retinitis,pneumonitis, gastrointestinal disorders and neurological diseases. CMVinfection is also associated with cardiovascular diseases and conditionsincluding restenosis and atherosclerosis.

The main disease caused by EBV is acute or chronic infectiousmononucleosis (glandular fever). Examples of other EBV or EBV associateddiseases include lymphoproliferative disease which frequently occurs inpersons with congenital or acquired cellular immune deficiency, X-linkedlymphoproliferative disease which occurs namely in young boys,EBV-associated B-cell tumours, Hodgkin's disease, nasopharyngealcarcinoma, Burkitt lymphoma, non-Hodgkin lymphoma, thymomas and oralhairy leukoplakia. EBV infections have also been found in associationwith a variety of epithelial-cell-derived tumours of the upper and lowerrespiratory tracts including the lung. EBV infection has also beenassociated with other diseases and conditions including chronic fatiguesyndrome, multiple sclerosis and Alzheimer's disease.

HHV-6 has been shown to be a causative agent of infantum subitum inchildren and of kidney rejection and interstitial pneumonia in kidneyand bone marrow transplant patients, respectively, and may be associatedwith other diseases such as multiple sclerosis. There is also evidenceof repression of stem cell counts in bone marrow transplant patients.HHV-7 is of undetermined disease aetiology.

Hepatitis B virus (HBV) is a viral pathogen of world-wide majorimportance. The virus is aetiologically associated with primaryhepatocellular carcinoma and is thought to cause 80% of the world'sliver cancer. Clinical effects of infection with HBV range fromheadache, fever, malaise, nausea, vomiting, anorexia and abdominalpains. Replication of the virus is usually controlled by the immuneresponse, with a course of recovery lasting weeks or months in humans,but infection may be more severe leading to persistent chronic liverdisease outlined above.

BRIEF SUMMARY OF THE INVENTION

According to a first aspect of the invention there is provided acompound of formula (I):

wherein:

-   R¹ is H;-   R² is selected from the group consisting of halo, alkyl, cycloalkyl,    alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het,    —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸,    —NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;    -   each R⁷ and R⁸ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —OR⁹, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹,        —C(S)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl,        —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,        —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R¹⁰,        —R¹⁰SO₂NR⁹R¹¹, —R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹ and —R¹⁰SO₂NHCOR⁹;    -   each R⁹ and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1–10, and        —R¹⁰NR¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl and alkynyl;    -   n is 0, 1 or 2;    -   Ay is aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;-   Y is N or CH;-   R³ and R⁴ are the same or different and are each independently    selected from the group consisting of H, halo, alkyl, cycloalkyl,    alkenyl, Ay, Het, —OR⁷, —OAy, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay,    —SO₂NHR⁹, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Het, —R¹⁰OR⁷, —R¹⁰OAy,    —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;-   q is 0, 1, 2, 3, 4 or 5;-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, cycloalkyl, alkenyl,    cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —C(O)R⁹, —CO₂R⁹,    —C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)Het, —C(O)NHR¹⁰Het,    —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸,    —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het,    —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹,    —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,    —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano,    nitro and azido; or    -   two adjacent R⁵ groups together with the atoms to which they are        bonded form a C₅₋₆ cycloalkyl or aryl;-   p is 1, 2 or 3; and-   each R⁶ is the same or different and is independently selected from    the group consisting of halo, alkyl, cycloalkyl, alkenyl,    cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay,    —OR¹⁰Het, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay,    —C(O)NHR¹⁰Ay, —C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸,    —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸,    —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het,    —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹,    —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het, —R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸,    —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,    —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹,    —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or    -   two adjacent R⁶ groups together with the atoms to which they are        bonded form a C₅₋₆cycloalkyl or a 5- or 6-membered heterocyclic        group containing 1 or 2 heteroatoms;-   wherein at least one R⁶ is selected from the group consisting of    —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; and-   wherein when Y is CH, R³ is not —NR⁷AY;    and pharmaceutically acceptable salts, solvates and physiologically    functional derivatives thereof.

According to another aspect, the present invention provides apharmaceutical composition comprising a compound of formula (I). In oneembodiment, the pharmaceutical composition further comprises apharmaceutically acceptable carrier or diluent. In one embodiment, thepharmaceutical composition further comprises an antiviral agent selectedfrom the group consisting of aciclovir and valaciclovir.

According to a third aspect, the present invention provides a method forthe prophylaxis or treatment of a herpes viral infection in an animal.The method comprises administering to the animal a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt, solvate or physiologically functional derivativethereof. The herpes viral infection may be herpes simplex virus 1,herpes simplex virus 2, cytomegalovirus, Epstein Barr virus, varicellazoster virus, human herpes virus 6, human herpes virus 7, or humanherpes virus 8.

According to a fourth aspect, the present invention provides a methodfor the prophylaxis or treatment of conditions or diseases associatedwith a herpes viral infection in an animal. The method comprisesadministering to the animal a therapeutically effective amount of thecompound of formula (I) or a pharmaceutically acceptable salt, solvateor physiologically functional derivative thereof.

According to a fifth aspect, the present invention provides a processfor preparing a compound of formula (I) wherein Y is N, R² is selectedfrom the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl,Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het —S(O)_(n)R⁹, —S(O)_(n)Ay,—S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het, —NHR¹⁰Ay,—R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; and R³ and R⁴ are H, said process comprisingreacting a compound of formula (IX):

-   -   wherein at least one R⁶ is selected from the group consisting of        —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het;

-   with an amine of formula (X):

According to a sixth aspect, the present invention provides a processfor preparing a compound of formula (I). The process comprises the stepsof:

-   (a) reacting the compound of formula (XXXII)

-   -   wherein p′ is 0, 1 or 2;        with diphenylphosphoryl azide in tert-butanol to give the        compound of formula (I-X)

-   (b) optionally cleaving the compound of formula (I-X) to give the    compound of formula (I-Y)

and

-   (c) optionally converting the compound of formula (I-Y) to a    compound of formula (I-Z)

-   -   wherein R^(6x) is selected from the group consisting of —NR⁷R⁸        where R⁷ and R⁸ are not both H, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and        —NHR¹⁰Het;        using conditions selected from the group consisting of cross        coupling, reductive amination, alkylation, acylation and        sulfonylation.

According to a seventh aspect, the present invention provides a processfor preparing a compound of formula (I) wherein Y is N; R² is selectedfrom the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl,Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het —S(O)_(n)R⁹, —S(O)_(n)Ay,—S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het, —NHR¹⁰Ay,—R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; R³ is selected from the group consisting of H,alkyl cycloalkyl, alkenyl, Ay, Het, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay,—SO₂NHR⁹, —NR⁷R⁸ (where R⁷ and R⁸ are not H), —NR⁷Ay (where R⁷ is notH), —R¹⁰OR⁷, —R¹⁰OAy, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; R⁴ is H; and at least oneR⁶ is selected from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet,—NHR¹⁰Ay and —NHR¹⁰Het. The process comprises the steps of:

-   a) reacting a compound of formula (XVI):

-   -   wherein each R⁶ is the same or different and is independently        selected from the group consisting of halo, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet,        —OR¹⁰Ay, —OR¹⁰Het, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)Ay,        —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay, —C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹,        —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)_(n)Ay,        —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay,        —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het,        —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹, —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het,        —R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,        —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,        —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano,        nitro and azido; or    -   two adjacent R⁶ groups together with the atoms to which they are        bonded form a C₅₋₆cycloalkyl or a 5- or 6-membered heterocyclic        group containing 1 or 2 heteroatoms;    -   wherein at least one R⁶ is selected from the group consisting of        halo, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; and        with an amine of formula (X):

to prepare a compound of formula (XVII)

-   -   wherein at least one R⁶ is selected from the group consisting of        halo, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; and

-   b) in the embodiment wherein no R⁶ is —NR⁷R⁸, —NR⁷Ay, —NHHet,    —NHR¹⁰Ay or —NHR¹⁰Het, replacing R⁶ halo of the compound of    formula (XVII) with an amine substituent selected from the group    consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het;    to prepare a compound of formula (I).

According to another aspect, the present invention provides a processfor preparing the compounds of formula (I) wherein Y is N; R² isselected from the group consisting of alkyl, cycloalkyl, alkenyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het —S(O)_(n)R⁹,—S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het,—NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; and at least one R⁶ is selected fromthe group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het.The process comprises the steps of:

-   a) reacting a compound of formula (XX):

-   -   wherein each R⁶ is the same or different and is independently        selected from the group consisting of halo, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet,        —OR¹⁰Ay, —OR¹⁰Het, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)Ay,        —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay, —C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹,        —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)_(n)Ay,        —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay,        —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het,        —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹, —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het,        —R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,        —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,        —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano,        nitro and azido; or    -   two adjacent R⁶ groups together with the atoms to which they are        bonded form a C₅₋₆cycloalkyl or a 5- or 6-membered heterocyclic        group containing 1 or 2 heteroatoms;    -   wherein at least one R⁶ is selected from the group consisting of        halo, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het;        with an amine of formula (X):

to prepare an intermediate compound;

-   b) oxidizing the intermediate compound to prepare a compound of    formula (XVII)

-   -   wherein at least one R⁶ is selected from the group consisting of        halo, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; and

-   c) in the embodiment wherein no R⁶ is —NR⁷R⁸, —NR⁷Ay, —NHHet,    —NHR¹⁰Ay or —NHR¹⁰Het, replacing R⁶ halo of the compound of    formula (XVII) with an amine substituent selected from the group    consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het;    to prepare a compound of formula (I).

According to another aspect, the present invention provides a processfor preparing the compounds of formula (I) wherein at least one R⁶ isselected from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ayand —NHR¹⁰Het. The process comprises the steps of:

-   a) reacting a compound of formula (XXII):

-   -   wherein each R⁶ is the same or different and is independently        selected from the group consisting of halo, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet,        —OR¹⁰Ay, —OR¹⁰Het, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)Ay,        —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay, —C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹,        —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)_(n)Ay,        —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay,        —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het,        —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹, —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het,        —R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,        —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,        —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano,        nitro and azido; or    -   two adjacent R⁶ groups together with the atoms to which they are        bonded form a C₅₋₆cycloalkyl or a 5- or 6-membered heterocyclic        group containing 1 or 2 heteroatoms;    -   wherein at least one R⁶ is selected from the group consisting of        halo, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; and    -   X¹ is chloro, bromo or iodo        with a compound of formula (XXIV):

-   -   wherein M² is selected from the group consisting of —B(OH)₂,        —B(ORa)₂, —B(Ra)₂, —Sn(Ra)₃, Zn-halide, ZnRa, and Mg-halide        where Ra is alkyl or cycloalkyl and halide is halo;        to prepare a compound of formula (XVII)

-   -   wherein at least one R⁶ is selected from the group consisting of        halo, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; and

-   b) in the embodiment wherein no R⁶ is —NR⁷R⁸, —NR⁷Ay, —NHHet,    —NHR¹⁰Ay or —NHR¹⁰Het, replacing R⁶ halo of the compound of    formula (XVII) with an amine substituent selected from the group    consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het;    to prepare a compound of formula (I).

According to another aspect, the present invention provides aradiolabeled compound of formula (I) or a pharmaceutically acceptablesalt, solvate or physiologically functional derivative thereof. In oneembodiment, the radiolabeled compound is tritiated. In another aspect,the present invention provides a biotinylated compound of formula (I) ora pharmaceutically acceptable salt, solvate or physiologicallyfunctional derivative thereof.

According to another aspect, the present invention provides a compoundof formula (I) for use in therapy. The present invention also provides acompound of formula (I) for the prophylaxis or treatment of a herpesviral infection in an animal. The present invention also provides acompound of formula (I) for the prophylaxis or treatment of conditionsor diseases associated with a herpes viral infection in an animal.

According to another aspect, the present invention provides the use of acompound of formula (I) for the preparation of a medicament forprophylaxis or treatment of a herpes viral infection in an animal,preferably humans. The present invention also provides the use of acompound of formula (I) for the preparation of a medicament for theprophylaxis or treatment of conditions or diseases associated with aherpes viral infection in an animal, preferably humans.

According to another aspect, the present invention provides apharmaceutical composition comprising a compound of formula (I) for usein the prophylaxis or treatment of a herpes viral infection in ananimal.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, “a compound of the invention” or “compound of formula(I)” means a compound of formula (I) or a pharmaceutically acceptablesalt, solvate, or physiologically functional derivative thereof.Similarly, with respect to isolatable intermediates such as for example,compounds of formula (IX), (XXXII), (XVI), (XVII), (XX), (XXII), (XXX),(XXXI) and (XXXII), the phrase “a compound of formula (number)” means acompound having that formula and pharmaceutically acceptable salts,solvates and physiologically functional derivatives thereof.

As used herein, the terms “alkyl” (and alkylene) refer to straight orbranched hydrocarbon chains containing from 1 to 8 carbon atoms.Examples of “alkyl” as used herein include, but are not limited to,methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl, andtert-butyl. Examples of “alkylene” as used herein include, but are notlimited to, methylene, ethylene, propylene, butylene, and isobutylene.“Alkyl” also includes substituted alkyl. The alkyl groups may beoptionally substituted with one or more substituents selected from thegroup consisting of mercapto, nitro, cyano and halo. Perhaloalkyl, suchas trifluoromethyl, is one preferred alkyl group.

As used herein, the term “cycloalkyl” refers to a non-aromaticcarbocyclic ring having from 3 to 8 carbon atoms and no carbon-carbondouble bonds. “Cycloalkyl” includes by way of example cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.“Cycloalkyl” also includes substituted cycloalkyl. The cycloalkyl mayoptionally be substituted on an available carbon with one or moresubstituents selected from the group consisting of mercapto, nitro,cyano, halo, and alkyl.

As used herein, the term “alkenyl” (and alkenylene) refers to straightor branched hydrocarbon chains containing from 2 to 8 carbon atoms andat least one and up to three carbon-carbon double bonds. Examples of“alkenyl” as used herein include, but are not limited to ethenyl andpropenyl. “Alkenyl” also includes substituted alkenyl. The alkenylgroups may optionally be substituted on an available carbon with one ormore substituents selected from the group consisting of mercapto, nitro,cyano, halo, and alkyl.

As used herein, the term “cycloalkenyl” refers to a non-aromaticcarbocyclic ring having from 3 to 8 carbon atoms (unless otherwisespecified) and up to 3 carbon-carbon double bonds. “Cycloalkenyl”includes by way of example cyclobutenyl, cyclopentenyl and cyclohexenyl.“Cycloalkenyl” also includes substituted cycloalkenyl. The cycloalkenylmay optionally be substituted on an available carbon with one or moresubstituents selected from the group consisting of mercapto, nitro,cyano, halo, and alkyl.

As used herein, the term “alkynyl” (and alkenylene) refers to straightor branched hydrocarbon chains containing from 2 to 8 carbon atoms andat least one and up to three carbon-carbon triple bonds. Examples of“alkynyl” as used herein include, but are not limited to ethynyl andpropynyl. “Alkynyl” also includes substituted alkynyl. The alkynylgroups may optionally be substituted on an available carbon with one ormore substituents selected from the group consisting of mercapto, nitro,cyano, halo, and alkyl.

The term “halo” or “halogen” refers to the elements fluorine, chlorine,bromine and iodine.

The term “aryl” refers to monocyclic carbocyclic groups and fusedbicyclic carbocyclic groups having from 5 to 12 carbon atoms and havingat least one aromatic ring. Examples of particular aryl groups includebut are not limited to phenyl and naphthyl. “Aryl” also includessubstituted aryl. Aryl groups may optionally be substituted on anavailable carbon with one or more substituents selected from the groupconsisting of halo, alkyl (including perhaloalkyl), alkenyl, cycloalkyl,cycloalkenyl, alkoxy, cycloalkoxy, amino, mercapto, hydroxy,alkylhydroxy, alkylamine, cycloalkylamine, carboxy, carboxamide,sulfonamide, Het, amidine, cyano, nitro and azido. Preferred aryl groupsaccording to the invention include but are not limited to phenyl andsubstituted phenyl.

The term “heterocyclic” (or “heterocycle”) refers to a monocyclicsaturated or unsaturated non-aromatic groups and fused bicyclicnon-aromatic groups, having the specified number of members andcontaining 1, 2, 3 or 4 heteroatoms selected from N, O and S. Examplesof particular heterocyclic groups include but are not limited totetrahydrofuran, dihydropyran, tetrahydropyran, pyran, oxetane,thietane, 1,4-dioxane, 1,3-dioxane, 1,3-dioxalane, piperidine,piperazine, tetrahydropyrimidine, pyrrolidine, morpholine,thiomorpholine, thiazolidine, oxazolidine, tetrahydrothiopyran,tetrahydrothiophene, and the like. “Heterocyclic” also includessubstituted heterocyclic. The heterocyclic group may be optionallysubstituted on an available carbon or heteroatom, with one or moresubstituents selected from the group consisting of halo, alkyl(including perhaloalkyl), alkenyl, cycloalkyl, cycloalkenyl, alkoxy,cycloalkoxy, amino, mercapto, hydroxy, alkylhydroxy, alkylamine,cycloalkylamine, carboxy, carboxamide, sulfonamide, Het, amidine, cyano,nitro and azido. Preferred heterocyclic groups according to theinvention include but are not limited to pyrrolidine, piperidine,morpholine, thiomorpholine and piperazine and subsituted variantsthereof.

The term “heteroaryl” refers to aromatic monocyclic groups and aromaticfused bicyclic groups wherein at least one ring is aromatic, having thespecified number of members (total carbon and heteroatoms) andcontaining 1, 2, 3, or 4 heteroatoms selected from N, O and S. Examplesof particular heteroaryl groups include but are not limited to furan,thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole,oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine,pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran,benzothiophene, indole, and indazole. “Heteroaryl” also includessubstituted heteroaryl. The heteroaryl group may optionally besubstituted on an available carbon or heteroatom with one or moresubstituents selected from the group consisting of halo, alkyl(including perhaloalkyl), alkenyl, cycloalkyl, cycloalkenyl, alkoxy,cycloalkoxy, amino, mercapto, hydroxy, alkylhydroxy, alkylamine,cycloalkylamine, carboxy, carboxamide, sulfonamide, Het, amidine, cyano,nitro and azido. Preferred heteroaryl groups according to the inventioninclude but are not limited to pyridine, furan, thiophene, pyrrole,imidazole, pyrazole, and pyrimidine, and substituted variants thereof.

The term “members” and variants thereof (e.g., “membered”)in the contextof heterocyclic and heteroaryl groups refers to the total atoms, carbonand heteroatoms N, O and/or S, which form the ring. Thus, an example ofa 6-membered heterocyclic ring is piperidine and an example of a6-membered heteroaryl ring is pyridine.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s)which occur and events that do not occur.

The present invention provides compounds of formula (I):

wherein:

-   R¹ is H;-   R² is selected from the group consisting of halo, alkyl, cycloalkyl,    alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het,    —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸,    —NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;    -   each R⁷ and R⁸ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —OR⁹, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹,        —C(S)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl,        —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,        —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R¹⁰,        —R¹⁰SO₂NR⁹R¹¹, —R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹ and —R¹⁰SO₂NHCOR⁹;    -   each R⁹ and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1–10, and        —R¹⁰NR¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl and alkynyl;    -   n is 0, 1 or 2;    -   Ay is aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;-   Y is N or CH;-   R³ and R⁴ are the same or different and are each independently    selected from the group consisting of H, halo, alkyl, cycloalkyl,    alkenyl, Ay, Het, —OR⁷, —OAy, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay,    —SO₂NHR⁹, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Het, —R¹⁰OR⁷, —R¹⁰OAy,    —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;-   q is 0, 1, 2, 3, 4 or 5;-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, cycloalkyl, alkenyl,    cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —C(O)R⁹, —CO₂R⁹,    —C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)Het, —C(O)NHR¹⁰Het,    —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸,    —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het,    —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹,    —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,    —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano,    nitro and azido; or    -   two adjacent R⁵ groups together with the atoms to which they are        bonded form a C₅₋₆ cycloalkyl or aryl;-   p is 1, 2 or 3; and-   each R⁶ is the same or different and is independently selected from    the group consisting of halo, alkyl, cycloalkyl, alkenyl,    cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay,    —OR¹⁰Het, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay,    —C(O)NHR¹⁰Ay, —C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸,    —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸,    —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het,    —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹,    —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het, —R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸,    —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,    —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹,    —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or    -   two adjacent R⁶ groups together with the atoms to which they are        bonded form a C₅₋₆cycloalkyl or a 5- or 6-membered heterocyclic        group containing 1 or 2 heteroatoms;-   wherein at least one R⁶ is selected from the group consisting of    —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; and-   wherein when Y is CH, R³ is not —NR⁷AY;    and pharmaceutically acceptable salts, solvates and physiologically    functional derivatives thereof.

In one preferred class of compounds of formula (I), Y is CH. In anotherpreferred embodiment, the compounds of formula (I) are defined wherein Yis N.

Compounds of formula (I) include those compounds defined wherein R²contains an aryl, heterocyclic or heteroaryl moiety. The groups Ay, Het,—OAy, —OHet, —OR¹⁰Het, —S(O)_(n)Ay, —S(O)_(n)Het, —NHHet, —NHR¹⁰Het,—NHR¹⁰Ay and —R¹⁰NR⁷Ay, are examples of groups containing an aryl,heterocyclic or heteroaryl moiety. In one embodiment, compounds of thepresent invention include those compounds defined wherein R² contains aheterocyclic or heteroaryl moiety such as Het, —OHet, —OR¹⁰Het—S(O)_(n)Het, —NHHet and —NHR¹⁰Het Another class of compounds of formula(I) includes those compounds defined wherein R² does not contain anaryl, heterocyclic or heteroaryl moiety. In such embodiments R² ispreferably selected from the group consisting of halo, alkyl,cycloalkyl, alkenyl, cycloalkenyl, —OR⁷, —S(O)_(n)R⁹, —S(O)_(n)NR⁷R⁸,—NR⁷R⁸ and —R¹⁰NR⁷R⁸. Yet another class of compounds include thosedefined wherein R² does not contain a heterocyclic or heteroaryl moietybut may contain an aryl moiety. In such embodiments, R² is preferablyselected from the group consisting of halo, alkyl, cycloalkyl, alkenyl,cycloalkenyl, Ay, —OR⁷, —OAy, —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)NR⁷R⁸,—NR⁷R⁸, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;

Preferably, R² is selected from the group consisting of Ay, Het, —OR⁷,—OAy, —OHet, —OR¹⁰Het —S(O)_(n)R⁹, —S(O)_(n)Ay, —NR⁷R⁸, —NHHet,—NHR¹⁰Het, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay, or any subset thereof. Morepreferably, R² is selected from the group consisting of Het, —NR⁷R⁸,—NHHet and NHR¹⁰Het, or any subset thereof. Particularly preferredcompounds of formula (I) are defined where R² is selected from the groupconsisting of —NR⁷R⁸ and Het, or any subset thereof. In one embodiment,R² is selected from the group consisting of —NR⁷R⁸.

In one preferred embodiment, R² is selected from the group consisting of—NH₂, —NH-alkyl, —NH-cycloalkyl, —N(alkyl)(alkyl), Het (e.g.,pyrrolidine), —NHHet and —NH-alkyl-Het, or any subset thereof. Morepreferably, R² is selected from the group consisting of —NH-alkyl,—NH-cycloalkyl, or any subset thereof.

Specific examples of some preferred R² groups are selected from thegroup consisting of —NH₂, —NH-methyl, —NH-ethyl, —NH-propyl,—NH-isopropyl, —NH-cyclopropyl, —NH-butyl, —NH-isobutyl,—NH-cyclopentyl, —NH-cyclohexyl, —NH(CH2)₂OCH₃, and pyrrolidine (e.g.,pyrrolidine bonded through N).

Preferably, R⁷ and R⁸ are each the same or different and areindependently selected from the group consisting of H, alkyl,cycloalkyl, R¹⁰-cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹, —C(O)R⁹ and R¹⁰CO₂R⁹,or any subset thereof. More preferably, R⁷ and R⁸ are each the same ordifferent and are independently selected from the group consisting of H,alkyl, cycloalkyl and R¹⁰-cycloalkyl, or any subset thereof. In oneembodiment, R⁷ and R⁸ are each the same or different and areindependently selected from the group consisting of H, alkyl andcycloalkyl, or any subset thereof.

Preferably R⁹ and R¹¹ are each the same or different and areindependently selected from the group consisting of H, alkyl,cycloalkyl, and —R¹⁰-cycloalkyl, or any subset thereof. More preferably,R⁹ and R¹¹ are each the same or different and are independently selectedfrom the group consisting of H and alkyl, or any subset thereof.

Preferably R¹⁰ is alkyl or cycloalkyl; more preferably alkyl.

In another embodiment, the compounds of formula (I) include thosecompounds defined where at least one of R₃ and R₄ contain a heterocyclicor heteroaryl moiety. Another embodiment includes those compounds offormula (I) where neither R₃ nor R₄ contain a heterocyclic or heteroarylmoiety.

R³ is preferably selected from the group consisting of H, halo, alkyl,—OR⁷, —CO₂R⁷ and —NR⁷R⁸, or any subset thereof. More preferably, R³ isselected from the group consisting of H, halo, alkyl, OR⁷, and —NR⁷R⁸,or any subset thereof. Most preferably R³ is H or alkyl. In oneembodiment R³ is H.

R⁴ is preferably selected from the group consisting of H, halo, alkyl,—OR⁷, —CO₂R⁷ and —NR⁷R⁸, or any subset thereof. More preferably R⁴ isselected from the group consisting of H, halo, alkyl, OR⁷, and —NR⁷R⁸,or any subset thereof. Most preferably, R⁴ is H or alkyl. In oneembodiment, R⁴ is H.

Preferably q is 0, 1 or 2. In one embodiment, q is 0. In one preferredembodiment q is 1. In one embodiment, q is 2 and the two R⁵ groups arebonded to adjacent carbon atoms, and optionally, together with the atomsto which they are bonded, they form a C₅₋₆ cycloalkyl or aryl. Thephrase “two adjacent R⁵ groups” refers to two R⁵ groups, each bonded toadjacent carbon atoms on the phenyl ring. In the embodiment where twoadjacent R⁵ groups together with the atoms to which they are bonded forma cycloalkyl or aryl, q is preferably 2, 3, 4 or 5; more preferably 2.

R⁵ may be in the ortho, meta or para position.

Another class of compounds of formula (I) includes those compoundsdefined wherein at least one R⁵ group contains an aryl, heterocyclic orheteroaryl moiety (preferably a heterocyclic or heteroaryl moiety) andtwo adjacent R⁵ groups together with the atoms to which they are bondeddo not form a C₅₋₆ cycloalkyl or aryl. Another class of compounds offormula (I) includes those compounds defined wherein q is 3, 4 or 5, atleast one R⁵ group contains an aryl, heterocyclic or heteroaryl moiety(preferably a heterocyclic or heteroaryl moiety) and two adjacent R⁵groups together with the atoms to which they are bonded do form a C₅₋₆cycloalkyl or aryl. A preferred class of compounds of formula (I)includes those compounds defined where no R⁵ group contains an aryl,heterocyclic or heteroaryl moiety (or in one embodiment no R⁵ groupcontains a heterocyclic or heteroaryl moiety) and two adjacent R⁵ groupstogether with the atoms to which they are bonded do not form a C₅₋₆cycloalkyl or aryl. Another class of compounds of formula (I) includesthose compounds defined wherein q is 2, 3, 4 or 5, no R⁵ group containsan aryl, heterocyclic or heteroaryl moiety (or in one embodiment no R⁵group contains a heterocyclic or heteroaryl moiety) and two adjacent R⁵groups together with the atoms to which they are bonded do form a C₅₋₆cycloalkyl or aryl.

In the embodiments where two adjacent R⁵ groups together with the atomsto which they are bonded form a cycloalkyl or aryl, each R⁵ group may bethe same or different and is preferrably selected from the groupconsisting of alkyl, and alkenyl. For example, in one embodiment twoadjacent R⁵ groups are alkyl and together with the atoms to which theyare bonded, they form a cycloalkyl group such as:

From this example, additional embodiments, including those where twoadjacent R⁵ groups together with the atoms to which they are bonded forman aryl group can be readily ascertained by those skilled in the artPreferably, the compounds of formula (I) are defined wherein twoadjacent R⁵ groups together with the atoms to which they are bonded donot form a C₅₋₆ cycloalkyl or aryl.

Preferably, each R⁵ group is the same or different and is independentlyselected from the group consisting of halo, alkyl, alkenyl, Ay, Het,—OR⁷, —CO₂R⁹, —C(O)NR⁷R⁸, —S(O)₂NR⁷R , —NR⁷R⁸, —NHR¹⁰Ay, cyano, nitroand azido, or any subset thereof. More preferably, each R⁵ group is thesame or different and is independently selected from the groupconsisting of halo, alkyl, —OR⁷, —NR⁷R⁸, Ay, Het, cyano and azido, orany subset thereof. Most preferably, each R⁵ group is the same ordifferent and is independently selected from the group consisting ofhalo, alkyl, —OR⁷ and cyano, or any subset thereof.

In particular, preferred embodiments of the compounds of formula (I) aredefined where R⁵ is H, halo (e.g., fluoro, chloro or bromo), alkyl(e.g., methyl), O-alkyl (e.g., O-methyl, O-isobutyl, and

cyano, —NH—CH₃, and —N(CH₃)₂.

p is preferably 1 or 2, more preferably 1.

R⁶ may be in the 4, 5 or 6 position. In one embodiment, p is 1 and R⁶ isin the C-5 position. In one embodiment, p is 1 and R⁶ is in the C-6position. In one embodiment p is 2 and one R⁶ is in the C-5 position andone R⁶ is in the C-6 position.

Another class of compounds of formula (I) includes those compoundsdefined wherein at least one R⁶ group contains an aryl, heterocyclic orheteroaryl moiety (preferably a heterocyclic or heteroaryl moiety) andtwo adjacent R⁶ groups together with the atoms to which they are bondeddo not form a C₅₋₆ cycloalkyl or a 5- or 6-membered heterocyclic groupcontaining 1 or 2 heteroatoms. Another class of compounds of formula (I)includes those compounds defined wherein p is 3, at least one R⁶ groupcontains an aryl, heterocyclic or heteroaryl moiety (preferably aheterocyclic or heteroaryl moiety) and two adjacent R⁶ groups togetherwith the atoms to which they are bonded do form a C₅₋₆ cycloalkyl or a5- or 6-membered heterocyclic group containing 1 or 2 heteroatoms. Apreferred class of compounds of formula (I) includes those compoundsdefined where no R⁶ group contains an aryl, heterocyclic or heteroarylmoiety (or in one embodiment no R⁶ group contains a heterocyclic orheteroaryl moiety) and two adjacent R⁶ groups together with the atoms towhich they are bonded do not form a C₅₋₆ cycloalkyl or a 5- or6-membered heterocyclic group containing 1 or 2 heteroatoms. Anotherclass of compounds of formula (I) includes those compounds definedwherein p is 2 or 3, no R⁶ group contains an aryl, heterocyclic orheteroaryl moiety (or in one embodiment no R⁶ group contains aheterocyclic or heteroaryl moiety) and two adjacent R⁶ groups togetherwith the atoms to which they are bonded do form a C₅₋₆ cycloalkyl or a5- or 6-membered heterocyclic group containing 1 or 2 heteroatoms.

In the embodiments where two adjacent R⁶ groups together with the atomsto which they are bonded form a C₅₋₆ cycloalkyl or a 5- or 6-memberedheterocyclic group containing 1 or 2 heteroatoms, each R⁶ group may bethe same or different and is preferrably selected from the groupconsisting of alkyl, alkenyl, —OR⁷, —NR⁷R⁸ and —S(O)_(n)R⁹. In onepreferred embodiment, when two R⁶ groups together with the atoms towhich they are bonded form a ring, it is a 5-6 membered heterocyclicgroup containing at least one N. For example, in one embodiment twoadjacent R⁶ groups are —NR⁷R⁸ and together with the atoms to which theyare bonded they form a heterocyclic group such as:

In another embodiment, one R⁶ group is —NR⁷R⁸ and another is alkyl andtogether with the atoms to which they are bonded they form aheterocyclic group such as:

In another embodiment two adjacent R⁶ groups are defined as —OR⁷, —NR⁷R⁸respectively and together with the atoms to which they are bonded, theyform a heterocyclic group such as:

In another embodiment two adjacent R⁶ groups are defined as —S(O)_(n)R⁹,—NR⁷R⁸ respectively and together with the atoms to which they arebonded, they form a heterocyclic group such as:

From these examples, additional embodiments can be readily ascertainedby those skilled in the art.

In one preferrred embodiment, each R⁶ is the same or different and isindependently selected from the group consisting of each R⁶ is the sameor different and is independently selected from the group consisting ofhalo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, Ay, Het, —OR⁷,—OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)Ay,—C(O)NR⁷Ay, —C(O)NHR¹⁰Ay, —C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹,—C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het,—S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het,—R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹, —R¹⁰—O—C(O)Ay,—R¹⁰—O—C(O)Het, —R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹,—R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,—R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano, nitroand azido. That is, preferably the compounds of formula (I) are definedwherein two adjacent R⁶ groups together with the atoms to which they arebonded do not form a C₅₋₆ cycloalkyl or a 5- or 6-member heterocyclicgroup containing 1 or 2 heteroatoms.

Preferably, each R⁶ is the same or different and is independentlyselected from the group consisting of halo, alkyl, Ay, Het, —OR⁷, —OAy,—OHet, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet,—NHR¹⁰Het and cyano, or any subset thereof; wherein at least one R⁶ isselected from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ayand —NHR¹⁰Het. More preferably, each R⁶ is the same or different and isindependently selected from the group consisting of halo, alkyl,—C(O)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het and cyano, or any subsetthereof; wherein at least one R⁶ is selected from the group consistingof —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het. Most preferably eachR⁶ is the same or different and is independently selected from the groupconsisting of halo, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het, orany subset thereof; wherein at least one R⁶ is selected from the groupconsisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het.

In one preferred embodiment, at least one R⁶ is selected from the groupconsisting of —NR⁷R⁸ and —NHHet; more preferably at least one R⁶ is—NR⁷R⁸.

More specific examples of preferred R⁶ groups include but are notlimited to —NH₂, —NHalkyl, —NHR¹⁰OR⁹, —NH-cycloalkyl, and —NH—SO₂-alkyl.In one preferred embodiment, R⁶ is selected from the group consisting of—NH₂, —NHCH(CH₃)₂, —NH-cyclopropyl, —NH-cyclopentyl, —NH(CH₂)₂—O—CH₃,and —NH—SO₂—CH₃.

It is to be understood that the present invention includes allcombinations and subsets of the particular and preferred groups definedhereinabove.

Preferred compounds of formula (I) include but are not limited to:

-   N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine;-   3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine;-   N-[3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-yl]methanesulfonamide;-   3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-6-amine;-   N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-6-amine;-   3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-isopropylpyrazolo[1,5-α]pyridin-6-amine;-   3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-(2-methoxyethyl)pyrazolo[1,5-α]pyridin-5-amine;-   3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-isopropylpyrazolo[1,5-α]pyridin-5-amine;-   N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]2-(4-methoxyphenyl)-pyrazolo[1,5-α]pyridin-5-amine;    and-   3-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-isopropyl-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine;-   4-Bromo-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine;-   4-Chloro-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine;-   4-Bromo-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine;-   4-Chloro-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine;-   N-Butyl-3-[2-(butylamino)pyridin-4-yl]-2-(4-fluorophenyl)pyrazolo-[1,5-α]pyridin-4-amine;-   4-{5-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-α]pyridin-2-yl}phenol;-   N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-isobutoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine;    and-   N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[4-(cyclopropylmethoxy)phenyl]pyrazolo[1,5-α]pyridin-5-amine;    pharmaceutically acceptable salts, solvates and physiologically    functional derivatives thereof.

Particularly preferred compounds of formula (I) include but are notlimited to:

-   N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-pyrazolo[1,5-α]pyridin-5-amine;-   3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-6-amine;-   N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)pyrazolo-[1,5-α]pyridin-5-amine;-   3-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-isopropyl-2-(4-methoxyphenyl)pyrazolo-[1,5-α]pyridin-5-amine;-   N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-isobutoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine;    and-   N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[4-(cyclopropylmethoxy)phenyl]pyrazolo[1,5-α]pyridin-5-amine;    and-   pharmaceutically acceptable salts, solvates and physiologically    functional derivatives thereof.

It will be appreciated by those skilled in the art that the compounds ofthe present invention may also be utilized in the form of apharmaceutically acceptable salt or solvate thereof. Thepharmaceutically acceptable salts of the compounds of formula (I)include conventional salts formed from pharmaceutically acceptableinorganic or organic acids or bases as well as quaternary ammoniumsalts. More specific examples of suitable acid salts includehydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric,fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic,tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic,glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic,naphthalene-2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic,malic, steroic, tannic and the like. Other acids such as oxalic, whilenot in themselves pharmaceutically acceptable, may be useful in thepreparation of salts useful as intermediates in obtaining the compoundsof the invention and their pharmaceutically acceptable salts. Morespecific examples of suitable basic salts include sodium, lithium,potassium, magnesium, aluminium, calcium, zinc,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, N-methylglucamine and procaine salts.

The term “solvate” as used herein refers to a complex of variablestoichiometry formed by a solute (a compound of formula (I)) and asolvent. Solvents, by way of example, include water, methanol, ethanol,or acetic acid.

The term “physiologically functional derivative” as used herein refersto any pharmaceutically acceptable derivative of a compound of thepresent invention, for example, an ester or an amide of a compound offormula (I), which upon administration to an animal, particularly amammal, such as a human, is capable of providing (directly orindirectly) a compound of the present invention or an active metabolitethereof. See, for example, Burger's Medicinal Chemistry And DrugDiscovery, 5th Edition, Vol 1: Principles And Practice.

Processes for preparing pharmaceutically acceptable salts, solvates andphysiologically functional derivatives of the compounds of formula (I)are conventional in the art. See, e.g., Burger's Medicinal Chemistry AndDrug Discovery 5th Edition, Vol 1: Principles And Practice.

As will be apparent to those skilled in the art, in the processesdescibed below for the preparation of compounds of formula (I), certainintermediates, may be in the form of pharmaceutically acceptable salts,solvates or physiologically functional derivatives of the compound.Those terms as applied to any intermediate employed in the process ofpreparing compounds of formula (I) have the same meanings as noted abovewith respect to compounds of formula (I). Processes for preparingpharmaceutically acceptable salts, solvates and physiologicallyfunctional derivatives of such intermediates are known in the art andare analogous to the process for preparing pharmaceutically acceptablesalts, solvates and physiologically functional derivatives of thecompounds of formula (I).

Certain compounds of formula (I) may exist in stereoisomeric forms (e.g.they may contain one or more asymmetric carbon atoms or may exhibitcis-trans isomerism). The individual stereoisomers (enantiomers anddiastereomers) and mixtures of these are included within the scope ofthe present invention. The present invention also covers the individualisomers of the compounds represented by formula (I) as mixtures withisomers thereof in which one or more chiral centres are inverted.Likewise, it is understood that compounds of formula (I) may exist intautomeric forms other than that shown in the formula and these are alsoincluded within the scope of the present invention.

The present invention further provides compounds of formula (I) for usein medical therapy, e.g. in the treatment or prophylaxis, includingsuppression of recurrence of symptoms, of a viral disease in an animal,e.g. a mammal such as a human. The compounds of formula (I) areespecially useful for the treatment or prophylaxis of viral diseasessuch as herpes viral infections. Herpes viral infections include, forexample, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2),cytomegalovirus (CMV), Epstein Barr virus (EBV), Varicella zoster virus(VZV), human herpes virus 6 (HHV-6), human herpes virus 7 (HHV-7), andhuman herpes virus 8 (HHV-8). Thus, the compounds of the invention arealso useful in the treatment or prophylaxis of the symptoms or effectsof herpes virus infections.

The compounds of the invention are useful in the treatment orprophylaxis of conditions or diseases associated with herpes virusinfections, particularly conditions or diseases associated with latentherpes virus infections in an animal, e.g., a mammal such as a human. Byconditions or diseases associated with herpes viral infections is meanta condition or disease, excluding the viral infection per se, whichresults from the presence of the viral infection, such as chronicfatigue syndrome which is associated with EBV infection; multiplesclerosis which has been associated with herpes viral infections such asEBV and HHV-6, which have been associated with HSV-1 infection. Furtherexamples of such conditions or diseases are described in the backgroundsection above.

In addition to those conditions and diseases, the compounds of thepresent invention may also be used for the treatment or prophylaxis ofcardiovascular diseases and conditions associated with herpes virusinfections, in particular atherosclerosis, coronary artery disease andrestenosis and specifically restenosis following angioplasty (RFA).Restenosis is the narrowing of the blood vessels which can occur afterinjury to the vessel wall, for example injury caused by balloonangioplasty or other surgical and/or diagnostic techniques, and ischaracterized by excessive proliferation of smooth muscle cells in thewalls of the blood vessel treated. It is thought that in many patientssuffering from RFA, viral infection, particularly by CMV and/or HHV-6 ofthe patient plays a pivotal role in the proliferation of the smoothmuscle cells in the coronary vessel treated. Restenosis can occurfollowing a number of surgical and/or diagnostic techniques, forexample, transplant surgery, vein grafting, coronary by-pass graftingand, most commonly following angioplasty.

There is evidence from work done both in vitro and in vivo, indicatingthat restenosis is a multifactorial process. Several cytokines andgrowth factors, acting in concert, stimulate the migration andproliferation of vascular smooth muscle cells (SMC) and production ofextracellular matrix material, which accumulate to occlude the bloodvessel. In addition growth suppressors act to inhibit the proliferationof SMC's and production of extracellular matrix material.

In addition, compounds of formula (I) may be useful in the treatment orprophylaxis of hepatitis B or hepatitis C viruses, human papilloma virus(HPV) and HIV.

Thus, the present invention provides a method for the treatment orprophylaxis of a viral infection in an animal such as a mammal (e.g., ahuman), particularly a herpes viral infection, which method comprisesadministering to the animal a therapeutically effective amount of thecompound of formula (I).

As used herein, the term “prophylaxis” refers to the complete preventionof infection, the prevention of occurrence of symptoms in an infectedsubject, the prevention of recurrence of symptoms in an infectedsubject, or a decrease in severity or frequency of symptoms of viralinfection, condition or disease in the subject.

As used herein, the term “treatment” refers to the partial or totalelimination of symptoms or decrease in severity of symptoms of viralinfection, condition or disease in the subject, or the elimination ordecrease of viral presence in the subject

As used herein, the term “therapeutically effective amount” means anamount of a compound of formula (I) which is sufficient, in the subjectto which it is administered, to treat or prevent the stated disease,condition or infection. For example, a therapeutically effective amountof a compound of formula (I) for the treatment of a herpes virusinfection is an amount sufficient to treat the herpes virus infection inthe subject.

The present invention also provides a method for the treatment orprophylaxis of conditions or diseases associated with a herpes viralinfection in an animal such as a mammal (e.g., a human), which comprisesadministering to the animal a therapeutically effective amount of thecompound of formula (I). In one embodiment, the present inventionprovides a method for the treatment or prophylaxis of chronic fatiguesyndrome and multiple sclerosis in an animal such as a mammal (e.g., ahuman), which comprises administering to the animal a therapeuticallyeffective amount of a compound of formula (I). The foregoing method isparticularly useful for the treatment or prophylaxis of chronic fatiguesyndrome and multiple sclerosis associated with latent infection with aherpes virus.

In another embodiment, the present invention provides a method for thetreatment or prophylaxis of a cardiovascular condition such asatherosclerosis, coronary artery disease or restenosis (particularlyrestenosis following surgery such as angioplasty), which comprisesadministering to the animal a therapeutically effective antiviral amountof the compound of formula (I).

The present invention further provides a method for the treatment orprophylaxis of hepatitis B or hepatitis C viruses in an animal such as amammal (e.g., a human), which comprises administering to the animal atherapeutically effective amount of the compound of formula (I).

The present invention further provides a method for the treatment orprophylaxis of human papilloma virus in an animal such as a mammal(e.g., a human), which comprises administering to the animal atherapeutically effective amount of the compound of formula (I).

The present invention further provides a method for the treatment orprophylaxis of HIV in an animal such as a mammal (e.g., a human), whichcomprises administering to the animal a therapeutically effective amountof the compound of formula (I).

The present invention also provides the use of the compound of formula(I) in the preparation of a medicament for the treatment or prophylaxisof a viral infection in an animal such as a mammal (e.g., a human),particularly a herpes viral infection; the use of the comound of formula(I) in the preparation of a medicament for the treatment of conditionsor diseases associated with a herpes viral infection; and the use of thecompound of formula (I) in the preparation of a medicament for thetreatment or prophylaxis of hepatitis B or hepatitis C viruses, humanpapilloma virus or HIV. In particular, the present invention alsoprovides the use of a compound of formula (I) in the preparation of amedicament for the treatment or prophylaxis of chronic fatigue syndromeor multiple sclerosis. In one embodiment, the present invention providesthe use of a compound of formula (I) in the preparation of a medicamentfor the treatment or prophylaxis of cardiovascular disease, such asrestenosis and atherosclerosis.

The compounds of formula (I) are conveniently administered in the formof pharmaceutical compositions. Such compositions may conveniently bepresented for use in conventional manner in admixture with one or morephysiologically acceptable carriers or diluents.

While it is possible that compounds of the present invention may betherapeutically administered as the raw chemical, it is preferable topresent the active ingredient as a pharmaceutical formulation orcomposition. The pharmaceutical composition may comprise a carrier ordiluent. The carrier(s) or diluent(s) must be “acceptable” in the senseof being compatible with the other ingredients of the formulation andnot deleterious to the recipient thereof.

Accordingly, the present invention further provides for a pharmaceuticalformulation or composition comprising a compound of formula (I). In oneembodiment, the pharmaceutical composition further comprises one or morepharmaceutically acceptable carriers or diluents and optionally, othertherapeutic and/or prophylactic ingredients.

The formulations include those suitable for oral, parenteral (includingsubcutaneous e.g. by injection or by depot tablet, intradermal,intrathecal, intramuscular e.g. by depot and intravenous), rectal andtopical (including dermal, buccal and sublingual) administrationalthough the most suitable route may depend upon for example thecondition, age, and disorder of the recipient as well as the viralinfection or disease being treated. The formulations may conveniently bepresented in unit dosage form and may be prepared by any of the methodswell known in the art of pharmacy. All methods include the step ofbringing into association a compound(s) of formula (I) (“activeingredient”) with the carrier which constitutes one or more accessoryingredients. In general the formulations are prepared by uniformly andintimately bringing into association the active ingredient with liquidcarriers or finely divided solid carriers or both and then, ifnecessary, shaping the product into the desired formulation.

Formulations suitable for oral administration may be presented asdiscrete units such as capsules, cachets or tablets (e.g. chewabletablets in particular for paediatric administration) each containing apredetermined amount of the active ingredient; as a powder or granules;as a solution or a suspension in an aqueous liquid or a non-aqueousliquid; or as an oil-in-water liquid emulsion or a water-in-oil liquidemulsion. The active ingredient may also be presented as a bolus,electuary or paste.

A tablet may be made by compression or moulding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed withother conventional excipients such as binding agents, (for example,syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch orpolyvinylpyrrolidone), fillers (for example, lactose, sugar,microcrystalline cellulose, maize-starch, calcium phosphate orsorbitol), lubricants (for example, magnesium stearate, stearic acid,talc, polyethylene glycol or silica), disintegrants (for example, potatostarch or sodium starch glycollate) or wetting agents, such as sodiumlauryl sulfate. Moulded tablets may be made by moulding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide slow or controlled release of the activeingredient therein. The tablets may be coated according to methodswell-known in the art.

Alternatively, the compounds of the present invention may beincorporated into oral liquid preparations such as aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, for example.Moreover, formulations containing these compounds may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may contain conventional additives such assuspending agents such as sorbitol syrup, methyl cellulose,glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats;emulsifying agents such as lecithin, sorbitan mono-oleate or acacia;non-aqueous vehicles (which may include edible oils) such as almond oil,fractionated coconut oil, oily esters, propylene glycol or ethylalcohol; and preservatives such as methyl or propyl p-hydroxybenzoatesor sorbic acid. Such preparations may also be formulated assuppositories, e.g., containing conventional suppository bases such ascocoa butter or other glycerides.

Formulations for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

The formulations may be presented in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilised) condition requiring only the addition of asterile liquid carrier, for example, water-for-injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions may beprepared from sterile powders, granules and tablets of the kindpreviously described.

Formulations for rectal administration may be presented as a suppositorywith the usual carriers such as cocoa butter, hard fat or polyethyleneglycol. Formulations suitable for topical or intranasal applicationinclude ointments, creams, lotions, pastes, gels, sprays, aerosols andoils. Suitable carriers for such formulations include petroleum jelly,lanolin, polyethyleneglycols, alcohols, and combinations thereof.

Formulations for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavoured base such as sucrose and acacia or tragacanth,and pastilles comprising the active ingredient in a base such as gelatinand glycerin or sucrose and acacia.

The compounds may also be formulated as depot preparations. Such longacting formulations may be administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection. Thus,for example, the compounds may be formulated with suitable polymeric orhydrophobic materials (for example as an emulsion in an acceptable oil)or ion exchange resins, or as sparingly soluble derivatives, forexample, as a sparingly soluble salt.

In addition to the ingredients particularly mentioned above, theformulations may include other agents conventional in the art havingregard to the type of formulation in question, for example thosesuitable for oral administration may include flavouring agents.

It will be appreciated that the amount of a compound of the inventionrequired for use in treatment will vary with the nature of the conditionbeing treated and the age and the condition of the patient and will beultimately at the discretion of the attendant physician or veterinarian.In general, however, doses employed for adult human treatment willtypically be in the range of 0.02–5000 mg per day, preferably 100–1500mg per day. The desired dose may conveniently be presented in a singledose or as divided doses administered at appropriate intervals, forexample as two, three, four or more sub-doses per day. The formulationsaccording to the invention may contain between 0.1–99% of the activeingredient, conveniently from 30–95% for tablets and capsules and 3–50%for liquid preparations.

The compound of formula (I) for use in the instant invention may be usedin combination with other therapeutic agents for example, non-nucleotidereverse transcriptase inhibitors, nucleoside reverse transcriptaseinhibitors, protease inhibitors and/or other antiviral agents. Theinvention thus provides in a further aspect the use of a combinationcomprising a compound of formula (I) with a further therapeutic agent inthe treatment of viral infections. Particular antiviral agents which maybe combined with the compounds of the present invention includeaciclovir, valaciclovir, famcyclovir, gancyclovir, docosanol, miribavir,amprenavir, lamivudine, zidovudine, and abacavir. Preferred antiviralagents for combining with the compounds of the present invention includeaciclovir and valaciclovir. Thus the present invention provides in afurther aspect, a combination comprising a compound of formula (I) andan antiviral agent selected from the group consisting of aciclovir andvalaciclovir; the use of such combination in the treatment of viralinfections and the preparation of a medicament for the treatment foviral infections, and a method of treating viral infections comprisingadministering a compound of formula (I) and an antiviral agent selectedfrom the group consisting of aciclovir and valaciclovir.

When a compound of formula (I) is used in combination with othertherapeutic agents, the compounds may be administered eithersequentially or simultaneously by any convenient route.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above optionallytogether with a pharmaceutically acceptable carrier or diluent comprisea further aspect of the invention. The Individual components of suchcombinations may be administered either sequentially or simultaneouslyin separate or combined pharmaceutical formulations. When combined inthe same formulation it will be appreciated that the two compounds mustbe stable and compatible with each other and the other components of theformulation and may be formulated for administration. When formulatedseparately they may be provided in any convenient formulation, in such amanner as are known for such compounds in the art.

When a compound of formula (I) is used in combination with a secondtherapeutic agent active against the viral infection, the dose of eachcompound may differ from that when the compound is used alone.Appropriate doses will be readily appreciated by those skilled in theart.

Compounds of formula (I) wherein Y is N, R² is selected from the groupconsisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷,—OAy, —OHet, —OR¹⁰Het —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het,—S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and—R¹⁰NR⁷Ay; R³ and R⁴ are H; and at least one R⁶ is selected from thegroup consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, and —NHR¹⁰Het, maybe conveniently prepared by the process outlined in Scheme 1 below.

wherein:

-   R¹ is H;-   R² is selected from the group consisting of alkyl, cycloalkyl,    alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het,    —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NHR⁷R⁸,    —NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;    -   each R⁷ and R⁸ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —OR⁹, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹,        —C(S)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl,        —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,        —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R¹⁰,        —R¹⁰SO₂NR⁹R¹¹, —R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹ and —R¹⁰SO₂NHCOR⁹;    -   each R⁹ and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1–10, and        —R¹⁰NR¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl and alkynyl;    -   n is 0, 1 or 2;    -   Ay is aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;-   Y is N;-   R³ and R⁴ are both H;-   q is 0, 1, 2, 3, 4 or 5;-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, cycloalkyl, alkenyl,    cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —C(O)R⁹, —CO₂R⁹,    —C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)Het, —C(O)NHR¹⁰Het,    —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸,    —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het,    —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹,    —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,    —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano,    nitro and azido; or    -   two adjacent R⁵ groups together with the atoms to which they are        bonded form a C₅₋₆ cycloalkyl or aryl;-   p is 1, 2 or 3; and-   each R⁶ is the same or different and is independently selected from    the group consisting of halo, alkyl, cycloalkyl, alkenyl,    cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay,    —OR¹⁰Het, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay,    —C(O)NHR¹⁰Ay, —C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸,    —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸,    —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het,    —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹,    —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het, —R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸,    —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,    —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹,    —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or    -   two adjacent R⁶ groups together with the atoms to which they are        bonded form a C₅₋₆cycloalkyl or a 5- or 6-membered heterocyclic        group containing 1 or 2 heteroatoms;-   wherein at least one R⁶ is selected from the group consisting of    —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; and-   wherein in the compounds of formulas (VIII), (IX) and (I), at least    one R⁶ is selected from the group consisting of —NR⁷R⁸, —NR⁷Ay,    —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; and-   Ra is alkyl or cycloalkyl.

Generally, the process for preparing the compounds of formula (I)wherein Y is N, R² is selected from the group consisting of alkyl,cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het—S(O)_(n)R⁹, —S(O)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸. —NHHet,—NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; and R³ and R⁴ are H; andat least one R⁶ is selected from the group consisting of —NR⁷R⁸, —NR⁷Ay,—NHHet, —NHR¹⁰Ay and —NHR¹⁰Het, (all formulas and all other variableshaving been defined above in connection with Scheme 1) comprises thesteps of:

-   (a) reacting a picoline of formula (XI) with a benzoylating agent of    formula (II) to prepare a compound of formula (III);-   (b) reacting the compound of formula (III) with a hydroxylamine    source to prepare a compound of formula (IV);-   (c) reacting the compound of formula (IV) with an acylating or    sulfonylating agent to prepare a compound of formula (V);-   (d) rearranging the compound of formula (V) to prepare a compound of    formula (VI);-   (e) acylating the compound of formula (VI) to prepare a compound of    formula (VII);-   (f) in the embodiment wherein no R⁶ in the compound of formula (VII)    is selected from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet,    —NHR¹⁰Ay and —NHR¹⁰Het (i.e., said at least on R⁶ is halo; herein    “R⁶ halo”) replacing the R⁶ halo of the compound of formula (VII)    with an amine substituent selected from the group consisting of    —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het to prepare a compound    of formula (VIII);-   (g) reacting the compound of formula (VIII) with a dimethylformamide    dialkyl acetal of formula (CH₃)₂NCH(ORa)₂ to prepare a compound of    formula (IX); and-   (h) reacting the compound of formula (IX) with a compound of    formula (X) to prepare a compound of formula (I).

More specifically, compounds of formula (I) wherein Y is N, R² isselected from the group consisting of alkyl, cycloalkyl, alkenyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het —S(O)_(n)R⁹,—S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het,—NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; R³ and R⁴ are H, and at least one R⁶is selected from the group consisting of halo, —NR⁷R⁸, —NR⁷Ay, —NHHet,—NHR¹⁰Ay and —NHR¹⁰Het can be prepared by reacting a compound of formula(IX) with a compound of formula (X).

-   -   wherein all variables are as defined above in connection with        Scheme 1.

This method can be readily carried out by mixing a compound of formula(IX) with a compound of formula (X) in a suitable solvent, optionally inthe presence of a base (preferably when the amidine is in a salt form),and heating the reaction to 50–150° C. Typical solvents include loweralcohols such as methanol, ethanol, isopropanol, dimethylformamide, orthe like. The base is typically a sodium alkoxide, potassium carbonate,or an amine base such as triethylamine. In one embodiment, the solventis dimethylformamide and the base is potassium carbonate, or an aminebase such as triethylamine.

Compounds of the formula (IX) may be conveniently prepared by reacting acompound of formula (VII) with a dimethylformamide dialkyl acetal offormula (CH₃)₂NCH(ORa)₂.

-   -   wherein all variables are as defined above in connection with        Scheme 1.

Typical dimethylformamide dialkylacetal compounds for use in this methodinclude but are not limited to dimethylformamide dimethylacetal anddimethylformamide di-tert-butylacetal. The reaction is carried out bymixing a compound of formula (VIII) with the dimethylformamide dialkylacetal, optionally with heating. As one skilled in the art willappreciate, this also encompasses the reaction of a compound of formula(VII) when at least one R⁶ in the compound of formula (VII) is selectedfrom the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and—NHR¹⁰Het. Thus, when the compound of formula (VII) is defined whereinat least one R⁶ is selected from the group consisting of —NR⁷R⁸, —NR⁷Ay,—NHHet, —NHR¹⁰Ay and —NHR¹⁰Het, then the following reaction of thecompound of formula (VII) with the amine is unnecessary, and thecompound of formula (VII) is in fact a compound of formula (VIII) forpurposes of preparing a compound of formula (I) pursuant to this method.

In the embodiment, wherein compounds of formula (VII) are defined suchthat no R⁶ is —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay or —NHR¹⁰Het (i.e., thecompounds of formula (VII) are defined wherein said at least one R⁶ ishalo; herein “R⁶ halo”) compounds of formula (VIII) may be prepared byreplacement of the halogen on the compounds of formula (VII) (i.e.,replacement of the R⁶ halo) with an amine substituent selected from thegroup consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het.

-   -   wherein all variables are as defined above in connection with        Scheme 1.

Typically the replacement is carried out by mixing the compound offormula (VII) with an amine nucleophile selected from the groupconsisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; andoptionally heating the reaction.

Alternatively, the process of converting a compound of formula (VII) toa compound of formula (VIII) is carried out by reacting a compound offormula (VII) with an imine in the presence of a palladium (0) source, abase and a suitable ligand, followed by hydrolysis to give a compound offormula (VIII). See J. Wolfe, et al., Tetrahedron Letters 38:6367–6370(1997). Typically the imine is benzophenoneimine, the palladium (0)source is tris(dibenzylideneacetone)-dipalladium(0), the base is sodiumtert-butoxide and the ligand isracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl. Suitable solventsinclude N,N-dimethylformamide and the like.

The reaction can also be carried out via an adaptation of proceduresfound in the literature (Wolfe, J. P.; Buchwald, S. L. J. Org. Chem.2000, 65, 1144) wherein a compound of formula (VII) is treated with anamine, a palladium (0) or nickel (0) source and a base in a suitablesolvent Suitable sources of palladium (0) include but are not limited topalladium(II) acetate and tris(dibenzylideneacetone) dipalladium (0).

Typical bases for use in the reaction include, for example sodiumtert-butoxide and cesium carbonate. Toluene is an example of a suitablesolvent.

The instant process for converting the R⁶ halo substituent in thecompounds of formula (VII) to the amine substituent selected from thegroup consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het, isdescribed as occurring toward the end of the synthesis, however, oneskilled in the art will readily appreciate that the conversion of thehalogen to the amine can occur at earlier stages in the process as well,using the same techniques as are described herein. For example, any ofthe halogenated intermediates may be converted to the amine analoguesprior to proceeding with the next step of the synthesis. This would ofcourse eliminate the need for performing this conversion later. Thevarious permutations of the foregoing synthesis wherein the conversionof the halogen to the amine occurs earlier in the synthesis arecontemplated by the instant invention and encompassed within its scope.Thus, the order of the foregoing steps of the synthesis is not criticalto obtaining the compounds of formula (I).

Compounds of formula (III) may be conveniently prepared from compoundsof the formula (VI) using an acylation procedure.

-   -   wherein all variables are as defined above in connection with        Scheme 1.

Typically the acylation is carried out by treating the compounds offormula (VI) with an acylating agent, optionally in the presence of anacid or Lewis acid catalyst in an inert solvent with optional heating.Typical acylating agents will be readily determined by those skilled inthe art. One preferred acylating agent is acetic anhydride. Lewis acidcatalysts are also known to those skilled in the art. One preferredLewis acid catalyst for use in this reaction is boron trifluoridediethyl etherate. A suitable solvent is toluene.

Compounds of formula (VI) are conveniently prepared by rearranging anazirine compound of formula (V).

-   -   wherein all variables are as defined above in connection with        Scheme 1.

The rearrangement of the azirines of formula (V) can be accomplished byheating a solution of the azirine of formula (V) in a suitable solventat a temperature of about 160–200° C. Suitable inert solvents include,but are not limited to, 1-methyl-2-pyrrolidinone, and1,2,4-trichlorobenzene. A more preferred method for rearrangement of theazirine of formula (V) to compounds of formula (VI) involves reactingthe compound of formula (V) with ferrous chloride (FeCl₂) or ferricchloride (FeCl₃). See PCT Publication No. WO 01/83479, published 8 Nov.2001 to GlaxoSmithKline Inc. This reaction is typically done in an inertsolvent with heating. A preferred solvent for this reaction is1,2-dimethoxyethane and the like.

Typically the azirines of formula (V) are prepared from oxime compoundsof formula (IV) by treatment with acylating or sulfonylating agents inthe presence of a base.

-   -   wherein all variables are as defined above in connection with        Scheme 1.

Typical acylating or sulfonylating agents include but are not limitedto, acetic anhydride, trifluoroacetic anhydride, methanesulfonylchloride, toluenesulfonyl chloride and the like. Typical bases include,but are not limited to, triethylamine, diisopropylethylamine, pyridine,and the like. The reaction may be carried out in an inert solvent suchas for example, chloroform, dichloromethane, toluene or the like.

The oxime compounds of formula (IV) are readily prepared by treatingketone compounds of formula (III) with a hydroxylamine source, in asuitable solvent, and optionally with a base.

-   -   wherein all variables are as defined above in connection with        Scheme 1.

Preferrably the hydroxylamine is hydroxylamine hydrochloride and thebase is an aqueous solution of sodium hydroxide. Suitable solventsinclude lower alcohols such as methanol, ethanol, or isopropanol.

The ketone compounds of formula (III) can be prepared by treatment of apicoline of formula (XI) with a benzoylating agent of formula (II) inthe presence of a base.

-   -   wherein all variables are as defined above in connection with        Scheme 1.

Preferred benzoylating agents of formula (II) include, but are notlimited to, benzoyl esters. An example of a preferred picoline is achloropicoline. An example of a suitable base is lithiumbis(trimethylsilyl)amide in an inert solvent such as tetrahydrofuran.Ketones such as those of formula (III) can be readily prepared usingprocedures known to one skilled in the art and/or described in theliterature (Cassity, R. P.; Taylor, L. T.; Wolfe, J. F. J. Org. Chem.1978, 2286).

In addition to the foregoing process for preparing certain compounds offormula (I), the present invention also provides certain intermediatecompounds for use in the preparation of such compounds of formula (I)according to the foregoing process. Such intermediates are representedin Scheme 1 above.

In a further embodiment of the present invention, compounds of formula(I) wherein Y is N; R² is selected from the group consisting of alkyl,cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet,—OR¹⁰Het—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸,—NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; and R³ and R⁴ areH, may be conveniently prepared by the process outlined in Scheme 1-Abelow.

wherein:

-   R¹ is H;-   R² is selected from the group consisting of alkyl, cycloalkyl,    alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het,    —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸,    —NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;    -   each R⁷ and R⁸ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —OR⁹, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹,        —C(S)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl,        —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,        —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R¹⁰,        —R¹⁰SO₂NR⁹R¹¹, —R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹ and —R¹⁰SO₂NHCOR⁹;    -   each R⁹ and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1–10, and        —R¹⁰NR¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl and alkynyl;    -   n is 0, 1 or 2;    -   Ay is aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;-   Y is N;-   R³ and R⁴ are both H;-   q is 0, 1, 2, 3, 4 or 5;-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, cycloalkyl, alkenyl,    cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —C(O)R⁹, —CO₂R⁹,    —C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)Het, —C(O)NHR¹⁰Het,    —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸,    —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het,    —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹,    —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,    —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano,    nitro and azido; or    -   two adjacent R⁵ groups together with the atoms to which they are        bonded form a C₅₋₆ cycloalkyl or aryl;-   p′ is 1, 2 or 3; and-   each R⁶ is the same or different and is independently selected from    the group consisting of halo, alkyl, cycloalkyl, alkenyl,    cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay,    —OR¹⁰Het, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay,    —C(O)NHR¹⁰Ay, —C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸,    —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸,    —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het,    —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹,    —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het, —R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸,    —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,    —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹,    —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or    -   two adjacent R⁶ groups together with the atoms to which they are        bonded form a C₅₋₆ cycloalkyl or a 5- or 6-membered heterocyclic        group containing 1 or 2 heteroatoms;-   R^(6x) is selected form the group consisting of —NR⁷R⁸ where R⁷ and    R⁸ are not both H, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; and-   Ra is alkyl or cycloalkyl.

Generally, the process for preparing the compounds of formula (I)wherein Y is N; R² is selected from the group consisting of alkyl,cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het—S(O)_(n)R⁹, —S(O)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet,—NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; and R³ and R⁴ are H; (allformulas and all other variables having been defined above in connectionwith Scheme 1-A) comprises the steps of:

-   (a) reacting a 2-chloro-5-trifluoromethylpyridine of formula (XI-A)    with an acetophenone of formula (XXVII) to prepare a compound of    formula (III-A);-   (b) reacting the compound of formula (III-A) with a hydroxylamine    source to prepare a compound of formula (IV-A);-   (c) reacting the compound of formula (IV-A) with an acylating or    sulfonylating agent to prepare a compound of formula (V-A);-   (d) rearranging the compound of formula (V-A) to prepare a compound    of formula (VI-A);-   (e) acylating the compound of formula (VI-A) to prepare a compound    of formula (VII-A);-   (f) reacting the compound of formula (VII-A) with a    dimethylformamide dialkyl acetal of formula (CH₃)₂NCH(ORa)₂ to    prepare a compound of formula (IX-A);-   (g) reacting the compound of formula (IX-A) with a compound of    formula (X) to prepare a compound of formula (XXX);-   (h) reacting the compound of formula (XXX) with sodium ethoxide to    prepare a compound of formula (XXXI);-   (i) reacting the compound of formula (XXXI) with an acid, followed    by hydrolysis of the resulting ester to give a compound of formula    (XXXII);-   (j) reacting the compound of formula (XXXII) with diphenylphosphoryl    azide in tert-butanol to give a compound of formula (I-X);-   (k) optionally cleaving the compound of formula (I-X) to give a    compound of formula (I-Y); and-   (l) optionally converting the compound of formula (I-Y) to a    compound of formula (I-Z) using conditions selected from the group    consisting of cross coupling, reductive amination, alkylation,    acylation and sulfonylation.

It will be appreciated by those skilled in the art that the compounds offormula (XXX), (XXXI) and (XXXII) in this and the following Schemes arein fact compounds of formula (I) when p′ is 1 or 2 and at least one R⁶is selected from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet,—NHR¹⁰Het and —NHR¹⁰Ay. When the compounds of formula (XXX), (XXXI) and(XXXII) are defined wherein p is 0 or no R⁶ is selected from the groupconsisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Het and —NHR¹⁰Ay, thecompounds of formula (XXX), (XXXI) and (XXXII) may be converted intocompounds of formula (I) using the following methods.

More specifically, compounds of formula (I) wherein Y is N; R² isselected from the group consisting of alkyl, cycloalkyl, alkenyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het—S(O)_(n)R⁹,—S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het,—NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; and R³ and R⁴ are H, can be preparedby a Curtius rearrangement well known to those skilled in the art.

The rearrangement can be performed by treating a compound of formula(XXXII) with diphosphoryl azide in tert-butanol in the presence of basewith heating. Other carboxylic acid derived migratory rearrangementscommonly known to one skilled in the art (such as the Lossen, Hofmann,and Schmidt reactions) may also be useful in this regard.

The foregoing reaction produces particular compounds of formula (I)(i.e., compounds of formula (I-X)) where at least one R⁶ is —NR⁷R⁸wherein R⁷ is H and R⁸ is CO₂R⁹ and R⁹ is tert-butyl. The compounds offormula (I-X) may optionally be further converted to other compounds offormula (I) (i.e., compounds of formula (I-Y)) where at least one R⁶ is—NR⁷R⁸ and R⁷ and R⁸ are both H, by acid catalyzed hydrolysis of thetert-butyl carbamate in a suitable solvent.

Suitable acids include hydrochloric acid and trifluoroacetic acid andthe like. Suitable solvents include dioxane, diethyl ether,tetrahydrofuran, dichloromethane and the like.

The compounds of formula (I-Y) may optionally be further converted toother compounds of formula (I) (i.e., compounds of formula (I-Z) whereat least one R^(6x) is selected from the group consisting of —NR⁷R⁸(wherein R⁷ and R⁸ are not both H), —NR⁷Ay, —NHHet, —NHR¹⁰Het and—NHR¹⁰Ay, by a cross coupling reaction (e.g., a Buchwald coupling),reductive amination, alkylation, acylation or sulfonylation, dependingupon the particular compound of formula (I-Z) that is desired.

One skilled in the art will readily be able to convert compounds offormula (I-Y) to compounds of formula (I-Z) using these generaltechniques.

Compounds of formula (XXXII), from which compounds of formula (I-X) aresynthesized, can be readily prepared by reacting a compound of formula(XXXI) with an acid, followed by hydrolysis of the resulting ester.

Suitable acids include but are not limited to p-toluenesulfonic acid,camphorsulfonic acid, pyridinium p-toluenesulfonic acid and the like. Anappropriate solvent such as acetone may be used. The hydrolysis can beperformed using lithium hydroxide and the like in a pure or mixedsolvent system including but not limited to solvents such astetrahydrofuran, methanol, and water.

Compounds of formula (XXXI) are prepared by treating a compound offormula (XXX) with an alkoxide salt in an alcohol solvent.

Suitable conditions for the foregoing reaction include the use of sodiumethoxide as the alkoxide, and ethanol as a choice solvent. The reactionmay optionally be heated to 60° C.

Compounds of formula (XXX) can be prepared using methods analogous tothose described above for the preparation of compounds of formula (I)according to Scheme 1, with the exception that the first step (i.e., thepreparation of compounds of formula (III-A)) involves the condensationof 2-chloro-5-trifluoromethylpyridine with the acetophenone of formula(XXVII) under basic conditions, in place of the reaction of the picolineof formula (XI) with the benzoylating agent of formula (II) as isemployed in the synthesis of the compound of formula (III) in Scheme 1.

In a further embodiment of the present invention, compounds of formula(I) wherein Y is N; R² is selected from the group consisting of alkyl,cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet,—OR¹⁰Het—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸,—NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; R³ is selectedfrom the group consisting of H, alkyl, cycloalkyl, alkenyl, —R¹⁰OR⁷,—NR⁷R⁸ (where R⁷ and R⁸ are not H), Ay, —R¹⁰OAy, —NR⁷Ay (where R⁷ is notH), —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay, —SO₂NHR⁹ andHet; R⁴ is H; and at least one R⁶ is selected from the group consistingof —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het, may be convenientlyprepared by the process outlined in Scheme 2 below.

wherein:

-   R¹ is H;-   R² is selected from the group consisting of alkyl, cycloalkyl,    alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet,    —OR¹⁰Het—S(O)_(n)R⁹, —S(O)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸,    —NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;    -   each R⁷ and R⁸ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —OR⁹, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹,        —C(S)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl,        —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,        —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R¹⁰,        —R¹⁰SO₂NR⁹R¹¹, —R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹ and —R¹⁰SO₂NHCOR⁹;    -   each R⁹ and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1–10, and        —R¹⁰NR¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl and alkynyl;    -   n is 0, 1 or 2;    -   Ay is aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;-   Y is N;-   R³ is selected from the group consisting of H, halo, alkyl,    cycloalkyl, alkenyl, —R¹⁰OR⁷, —NR⁷R⁸ (where R⁷ and R⁸ are not H),    Ay, —R¹⁰OAy, —NR⁷Ay, (where R⁷ is not H), —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay,    —C(O)R⁷, —CO₂R⁷, —CO₂Ay, —SO₂NHR⁹ and Het;-   R⁴ is H;-   q is 0, 1, 2, 3, 4 or 5;-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, cycloalkyl, alkenyl,    cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —C(O)R⁹, —CO₂R⁹,    —C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)Het, —C(O)NHR¹⁰Het,    —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸,    —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het,    —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹,    —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,    —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano,    nitro and azido; or    -   two adjacent R⁵ groups together with the atoms to which they are        bonded form a C₅₋₆ cycloalkyl or aryl;-   p is 1, 2 or 3; and-   each R⁶ is the same or different and is independently selected from    the group consisting of halo, alkyl, cycloalkyl, alkenyl,    cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay,    —OR¹⁰Het, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay,    —C(O)NHR¹⁰Ay, —C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸,    —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸,    —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het,    —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹,    —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het, —R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸,    —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,    —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹,    —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or    -   two adjacent R⁶ groups together with the atoms to which they are        bonded form a C₅₋₆ cycloalkyl or a 5- or 6-membered heterocyclic        group containing 1 or 2 heteroatoms;-   wherein in the compounds of formulas (XI), (III), (IV), (V), (VI),    (XIII), (XV), (XVI) and (XVII) at least one R⁶ is selected from the    group consisting of halo, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and    —NHR¹⁰Het;-   wherein in the compounds of formula (I) at least one R⁶ is selected    from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and    —NHR¹⁰Het; and-   M¹ is Li, Mg-halide or cerium-halide, wherein halide is halo.

Generally, the process for preparing compounds of formula (I) wherein Yis N; R² is selected from the group consisting of alkyl, cycloalkyl,alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het—S(O)_(n)R⁹,—S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het,—NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; R³ is selected from the groupconsisting of H, alkyl, cycloalkyl, alkenyl, —R¹⁰OR⁷, —NR⁷R⁸ (where R⁷and R⁸ are not H), Ay, —R¹⁰OAy, —NR⁷Ay (where R⁷ is not H), —R¹⁰NR⁷R⁸,—R¹⁰NR⁷Ay, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay, —SO₂NHR⁹ and Het; R⁴ is H;and at least one R⁶ is selected from the group consisting of —NR⁷R⁸,—NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het, (all other variables having beendefined above in connection with Scheme 2), comprises the followingsteps:

-   (a) reacting a picoline of formula (XI) with a benzoylating agent of    formula (II) to prepare a compound of formula (III);-   (b) reacting the compound of formula (III) with a hydroxylamine    source to prepare a compound of formula (IV);-   (c) reacting the compound of formula (IV) with an acylating or    sulfonylating agent to prepare a compound of formula (V);-   (d) rearranging the compound of formula (V) to prepare a compound of    formula-   (e) formylating the compound of formula (VI) to prepare a compound    of formula (XIII);-   (f) reacting the compound of formula (XIII) with a compound of    formula (XIV) to prepare a compound of formula (XV);-   (g) oxidizing the compound of formula (XI) to prepare a compound of    formula (XVI);-   (h) reacting a compound of formula (XVI) with a compound of    formula (X) to prepare a compound of formula (XVII); and-   (i) in the embodiment wherein no R⁶ in the compound of    formula (XVII) is —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay or —NHR¹⁰Het,    replacing the R⁶ halo of the compound of formula (XVII) with an    amine substituent selected from the group consisting of —NR⁷R⁸,    —NR⁷Ay, —NHHet, —NHR¹⁰Het and —NHR¹⁰Ay to prepare a compound of    formula (I), wherein at lest one R⁶ is selected from the group    consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het.

It will be appreciated by those skilled in the art that the compounds offormula (XVII) in this and the following Schemes, are in fact compoundsof formula (I) when p is 1 or 2 and at least one R⁶ is selected from thegroup consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het. Whenthe compounds of formula (XVII) are defined wherein p is 0 or no R⁶ isselected from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Hetand —NHR¹⁰Ay, the compounds of formula (XVII) or pharmaceuticallyacceptable salts, solvates and physiologically functional derivativesthereof may be converted into compounds of formula (I) using thefollowing methods. While the chemical formulas of the compounds offormula (XVII) and the compounds of formula (I) are represented as thesame, the definition of the variable R⁶ differs; with respect to thecompounds of formula (XVII) at least one R⁶ must be selected from thegroup consisting of halo, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and—NHR¹⁰Het, whereas in the compounds of formula (I) at least one R⁶ mustbe selected from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet,—NHR¹⁰Ay and —NHR¹⁰Het.

The foregoing process and following Schemes involving the conversion ofthe R⁶ halo substituent on the compounds of formula (XVII) to the aminesubstituent (—NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Het or —NHR¹⁰Ay) in thecompounds of formula (I) is described as occurring at the end of thesynthesis. However, one skilled in the art will readily appreciate thatthe conversion of the halogen to the amine substituent can occur atearlier stages in the process as well, using the same techniques as aredescribed herein. For example, any of the halogenated intermediates maybe converted to the amine analogues prior to proceeding with the nextstep of the synthesis. This would of course eliminate the need forperforming this conversion as the final step. The various permutationsof the foregoing synthesis wherein the conversion of the halogen to theamine occurs earlier in the synthesis are contemplated by the instantinvention and encompassed within its scope. Thus, the order of theforegoing steps of the synthesis is not critical to obtaining thecompounds of formula (I). In the embodiments wherein the conversion ofthe halogen substituent to the amine occurs earlier in the synthesis, orwhere at least one R⁶ in the compound of formula (XVI) is selected fromthe group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het,the compounds of formula (I) are a direct result of the reaction of thecompound of formula (XVI) and a compound of formula (X) and theamination step depicted last is not required.

More specifically, wherein no R⁶ in the compound of formula (XVII) isselected from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ayand —NHR¹⁰Het (i.e., said at least one R⁶ is halo; herein “R⁶ halo”),compounds of formula (I) wherein Y is N; R² is selected from the groupconsisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷,—OAy, —OHet, —OR¹⁰Het—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het,—S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and—R¹⁰NR⁷Ay; R³ is selected from the group consisting of H, alkyl,cycloalkyl, alkenyl, —R¹⁰OR⁷, —NR⁷R⁸ (where R⁷ and R⁸ are not H), Ay,—R¹⁰Ay, —NR⁷Ay (where R⁷ is not H), —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —C(O)R⁷,—C(O)Ay, —CO₂R⁷, —CO₂Ay, —SO₂NHR⁹ and Het; R⁴ is H; and at least one R⁶is selected from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet,—NHR¹⁰Ay and —NHR¹⁰Het, may be prepared by replacing the R⁶ halo on thecompounds of formula (XVII) with an amine substituent selected from thegroup consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Het and —NHR¹⁰Ay.

Typically the replacement is carried out by mixing the compound offormula (XVII) with an amine nucleophile selected from the groupconsisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; andoptionally heating the reaction.

Alternatively, the process of converting compounds of formula (XVII) tocompounds of formula (I) is carried out by reacting a compound offormula (XVII) with an imine in the presence of a palladium (0) source,a base and a suitable ligand, followed by hydrolysis to give a compoundof formula (I). See J. Wolfe, et al., Tetrahedron Letters 38:6367–6370(1997). Typically the imine is benzophenoneimine, the palladium (0)source is tris(dibenzylideneacetone)dipalladium(0), the base is sodiumtert-butoxide and the ligand isracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl. Suitable solventsinclude N,N-dimethylformamide and the like.

The reaction can also be carried out via an adaptation of proceduresfound in the literature (Wolfe, J. P.; Buchwald, S. L J. Org. Chem.2000, 65, 1144) wherein a compound of the formula (XVII) is treated withan amine, a palladium (0) or nickel (0) source and a base in a suitablesolvent. Suitable sources of palladium (0) include but are not limitedto palladium(II) acetate and tris(dibenzylideneacetone) dipalladium (0).Typical bases for use in the reaction include, for example sodiumtert-butoxide and cesium carbonate. Toluene is an example of a suitablesolvent.

Compounds of formula (XVII) can be prepared by reacting a compound offormula (XVI) with a compound of formula (X).

-   -   wherein all variables are as defined above in connection with        Scheme 2. As will be apparent to those skilled in the art, when        compounds of formula (XVI) are defined where at least one R⁶ is        selected from the group consisting of NR⁷R⁸, —NR⁷Ay, —NHHet,        —NHR¹⁰Ay and —NHR¹⁰Het, the compounds of formula (I) result        directly from the foregoing reaction.

This method can be readily carried out by mixing a compound of formula(XVI) with a compound of formula (X) in a suitable solvent, optionallyin the presence of a base. The reaction may be heated to 50–150° C. orperformed at ambient temperature. Typical solvents include but are notlimited to lower alcohols such as methanol, ethanol, isopropanol and thelike. Typical bases include for example, sodium alkoxide, potassiumcarbonate, or an amine base such as triethylamine. In anotherembodiment, the solvent is N,N-dimethylformamide and the base ispotassium carbonate, or an amine base such as triethylamine.

Compounds of formula (XVI) may be conveniently prepared by oxidation ofa compound of formula (XV).

-   -   wherein all variables are as defined above in connection with        Scheme 2.

Preferred oxidizing agents include but are not limited to, manganesedioxide, and the like, in an inert solvent. Suitable inert solventsinclude but are not limited to, dichloromethane, chloroform,N,N-dimethylformamide, ether, and the like.

Compounds of formula (XV) may be conveniently prepared by reacting acompound of formula (XIII) with a compound of formula (XIV).

-   -   wherein all variables are as defined above in connection with        Scheme 2.

Preferred metals (M¹) in the compounds of formula (XIV) include but arenot limited to, lithium, magnesium(II) halides, cerium(III) halides, andthe like. Compounds of formula (XIV) may be purchased from commercialsources or prepared by methods known to one skilled in the art.

Compounds of formula (XIII) may be conveniently prepared from compoundsof formula (VI) by a formylation procedure.

-   -   wherein all variables are as defined above in connection with        Scheme 2.

Typically the formylation is carried out via the Vilsmeier-Haackreaction. The Vilsmeier-Haack reagents can be purchased from commercialsources or prepared in situ. Preferable conditions include, but are notlimited to treating compounds of formula (VI) with a premixed solutionof phosphorous oxychloride in N,N-dimethylformamide optionally withheating the reaction to 50–150° C. The compounds of formula (VI) areprepared by the process described above in connection with Scheme 1.

In addition to the foregoing process for preparing certain compounds offormula (I), the present invention also provides certain intermediatecompounds for use in the preparation of such compounds of formula (I)according to the foregoing process. Such intermediates are depicted inScheme 2 above.

In a further embodiment of the present invention, compounds of formula(I) wherein Y is N; R² is selected from the group consisting of alkyl,cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet,—OR¹⁰Het—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸,—NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; R³ is selectedfrom the group consisting of H, alkyl, cycloalkyl, alkenyl, Ay, Het,—C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay, —SO₂NHR⁹, —NR⁷R⁸ (where R⁷ and R⁸ arenot H), —NR⁷Ay (where R⁷ is not H), —R¹⁰OR⁷, —R¹⁰OAy, —R¹⁰NR⁷R⁸ and—R¹⁰NR⁷Ay; and R⁴ is H, may be conveniently prepared by the processoutlined in Scheme 2-A below.

-   wherein:-   R¹ is H;-   R² is selected from the group consisting of halo, alkyl, cycloalkyl,    alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het,    —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸,    NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;    -   each R⁷ and R⁸ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —OR⁹, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹,        —C(S)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl,        —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,        —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R¹⁰,        —R¹⁰SO₂NR⁹R¹¹, —R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹ and —R¹⁰SO₂NHCOR⁹;    -   each R⁹ and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1–10, and        —R¹⁰NR¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl and alkynyl;    -   n is 0, 1 or 2;    -   Ay is aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;-   Y is N;-   R³ is selected from the group consisting of H, halo, alkyl,    cycloalkyl, alkenyl, —R¹⁰OR⁷, —NR⁷R⁸ (where R⁷ and R⁸ are not H),    Ay, —R¹⁰OAy, —NR⁷Ay, (where R⁷ is not H), —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay,    —C(O)R⁷, —CO₂R⁷, —CO₂Ay, —SO₂NHR⁹ and Het;-   R⁴ is H;-   q is 0, 1, 2, 3, 4 or 5;-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, cycloalkyl, alkenyl,    cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —C(O)R⁹, —CO₂R⁹,    —C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)Het, —C(O)NHR¹⁰Het,    —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸,    —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het,    —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹,    —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,    —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano,    nitro and azido; or    -   two adjacent R⁵ groups together with the atoms to which they are        bonded form a C₅₋₆ cycloalkyl or aryl;-   p′ is 1, 2 or 3; and-   each R⁶ is the same or different and is independently selected from    the group consisting of halo, alkyl, cycloalkyl, alkenyl,    cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay,    —OR¹⁰Het, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁹, —C(O)Ay, —C(O)NR⁷Ay,    —C(O)NHR¹⁰Ay, —C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸,    —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸,    —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het,    —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹,    —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het, —R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸,    —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,    —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹,    —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or    -   two adjacent R⁶ groups together with the atoms to which they are        bonded form a C₅₋₆ cycloalkyl or a 5- or 6-membered heterocyclic        group containing 1 or 2 heteroatoms;-   R^(6x) is selected from the group consisting of —NR⁷R⁸ where R⁷ and    R⁸ are not both H, —NR⁷Ay, —NHHet, —NHR¹⁰Het and —NHR¹⁰Ay; and-   M¹ is Li, Mg-halide or cerium-halide, wherein halide is halo.

Generally, the process for preparing compounds of formula (I) wherein Yis N; R² is selected from the group consisting of alkyl, cycloalkyl,alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het—S(O)_(n)R⁹,—S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het,—NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; R³ is selected from the groupconsisting of H, alkyl, cycloalkyl, alkenyl, Ay, Het, —C(O)R⁷, —C(O)Ay,—CO₂R⁷, —CO₂Ay, —SO₂NHR⁹, —NR⁷R⁸ (where R⁷ and R⁸ are not H), —NR⁷Ay(where R⁷ is not H), —R¹⁰OR⁷, —R¹⁰OAy, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; and R⁴is H, (all other variables having been defined above in connection withScheme 2-A), comprises the following steps:

-   (a) reacting a 2-chloro-5-trifluoromethylpyridine of formula (XI-A)    with an acetophenone of formula (XXVII) to prepare a compound of    formula (III-A);-   (b) reacting the compound of formula (III-A) with a hydroxylamine    source to prepare a compound of formula (IV-A);-   (c) reacting the compound of formula (IV-A) with an acylating or    sulfonylating agent to prepare a compound of formula (V-A);-   (d) rearranging the compound of formula (V-A) to prepare a compound    of formula (VI-A);-   (e) formulating the compound of formula (VI-A) to prepare a compound    of formula (XIII-A);-   (f) reacting the compound of formula (XIII-A) with a compound of    formula (XIV) to prepare a compound of formula (XV-A);-   (g) oxidizing the compound of formula (XV-A) to prepare a compound    of formula (XVI-A);-   (h) reacting a compound of formula (XVI-A) with a compound of    formula (X) to prepare a compound of formula (XXX);-   (i) reacting the compound of formula (XXX) with sodium ethoxide to    prepare a compound of formula (XXXI);-   (j) reacting the compound of formula (XXXI) with an acid, followed    by hydrolysis of the resulting ester to give a compound of formula    (XXXII);-   (k) reacting the compound of formula (XXXII) with diphenylphosphoryl    azide in tert-butanol to give a compound of formula (I-X);-   (l) optionally cleaving the compound of formula (I-X) to give a    compound of formula (I-Y); and-   (m) optionally converting the compound of formula (I-Y) to a    compound of formula (I-Z) using conditions selected from the group    consisting of cross coupling, reductive amination, alkylation,    acylation and sulfonylation.

In particular, compounds of formula (I) wherein Y is N; R² is selectedfrom the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl,Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het—S(O)_(n)R⁹, —S(O)_(n)Ay,—S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het, —NHR¹⁰Ay,—R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; R³ is selected from the group consisting of H,alkyl, cycloalkyl, alkenyl, Ay, Het, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay,—SO₂NHR⁹, —NR⁷R⁸ (where R⁷ and R⁸ are not H), —NR⁷Ay (where R⁷ is notH), —R¹⁰OR⁷, —R¹⁰OAy, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; and R⁴ is H, can beprepared by converting the compounds of formula (XXX) to compounds offormula (I) using the methods described above in connection with theprocess of Scheme 1-A.

Compounds of formula (XXX) can be prepared using methods analogous tothose described above for the preparation of compounds of formula (XVII)according to Scheme 2, with the exception that the first step (i.e., thepreparation of compounds of formula (III-A)) involves the condensationof 2-chloro-5-trifluoromethylpyridine with an acetophenone of formula(XXVII) under basic conditions, in place of the reaction of the picolineof formula (XI) with the benzoylating agent of formula (II) as isemployed in the synthesis of compounds of formula (VI) in Scheme 1.

The compounds of formula (XXX) can be converted to compounds of formula(I) using the methods described above in connection with Scheme (1-A).

Compounds of formula (I) wherein Y is N; R² is selected from the groupconsisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷,—OAy, —OHet, —OR¹⁰Het—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het,—S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and—R¹⁰NR⁷Ay; and at least one R⁶ is selected from the group consisting of—NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het, may be convenientlyprepared by the process outlined in Scheme 3 below.

-   wherein:-   R¹ is H;-   R² is selected from the group consisting of halo, alkyl, cycloalkyl,    alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het,    —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸,    NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;    -   each R⁷ and R⁸ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —OR⁹, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹,        —C(S)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl,        —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,        —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R¹⁰,        —R¹⁰SO₂NR⁹R¹¹, —R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹ and —R¹⁰SO₂NHCOR⁹;    -   each R⁹ and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1–10, and        —R¹⁰NR¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl and alkynyl;    -   n is 0, 1 or 2;    -   Ay is aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;-   Y is N;-   R³ and R⁴ are the same or different and are each independently    selected from the group consisting of H, halo, alkyl, cycloalkyl,    alkenyl, Ay, Het, —OR⁷, —OAy, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂AY,    —SO₂NHR⁹, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Het, —R¹⁰OR⁷, —R¹⁰OAy,    —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;-   q is 0, 1, 2, 3, 4 or 5;-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, cycloalkyl, alkenyl,    cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —C(O)R⁹, —CO₂R⁹,    —C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)Het, —C(O)NHR¹⁰Het,    —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸,    —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het,    —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹,    —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,    —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano,    nitro and azido; or    -   two adjacent R⁵ groups together with the atoms to which they are        bonded form a C₅₋₆ cycloalkyl or aryl;-   p is 1, 2 or 3; and-   each R⁶ is the same or different and is independently selected from    the group consisting of halo, alkyl, cycloalkyl, alkenyl,    cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay,    —OR¹⁰Het, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁹, —C(O)Ay, —C(O)NR⁷Ay,    —C(O)NHR¹⁰Ay, —C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸,    —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸,    —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het,    —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹,    —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het, —R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸,    —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,    —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹,    -   —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or    -   two adjacent R⁶ groups together with the atoms to which they are        bonded form a C₅₋₆ cycloalkyl or a 5- or 6-membered heterocyclic        group containing 1 or 2 heteroatoms;-   wherein in the compounds of formulas (XIII), (XIX), (XX) and (VII)    at least one R⁶ is selected from the group consisting of halo,    —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het;-   wherein in the compounds of formula (I) at least one R⁶ is selected    from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and    —NHR¹⁰Het; and-   M¹ is Li, Mg-halide or cerium-halide, wherein halide is halo.

Generally, the process for preparing compounds of formula (I) wherein Yis N; R² is selected from the group consisting of alkyl, cycloalkyl,alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het—S(O)_(n)R⁹,—S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het,—NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; and at least one R⁶ is selected fromthe group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het,(all formulas and all other variables having been defined above inconnection with Scheme 3), comprises the following steps:

-   (a) reacting a picoline of formula (XI) with a benzoylating agent of    formula (II) to prepare a compound of formula (III);-   (b) reacting the compound of formula (III) with a hydroxylamine    source to prepare a compound of formula (IV);-   (c) reacting the compound of formula (IV) with an acylating or    sulfonylating agent to prepare a compound of formula (V);-   (d) rearranging the compound of formula (V) to prepare a compound of    formula (VI);-   (e) formylating the compound of formula (VI) to prepare a compound    of formula (XIII);-   (f) reacting a compound of formula (XIII) with a compound of    formula (XVIII) to prepare a compound of formula (XIX);-   (g) oxidizing the compound of formula (XIX) to prepare a compound of    formula (XX);-   (h) reacting a compound of formula (XX) with a compound of    formula (X) followed by oxidative aromatization to prepare the    compound of formula (XVII); and-   (i) in the embodiment wherein no R⁶ is selected from the group    consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het (i.e.,    R⁶ halo) replacing the R⁶ halo of the compound of formula (XVII)    with an amine substituent selected from the group consisting of    —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het to prepare a compound    of formula (I).

More specifically, wherein no R⁶ in the compound of formula (XVII) isselected from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ayand —NHR¹⁰Het (i.e., said at least one R⁶ is halo; “R⁶ halo”), thecompounds of formula (I) wherein Y is N; R² is selected from the groupconsisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷,—OAy, —OHet, —OR¹⁰Het—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het,—S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and—R¹⁰NR⁷Ay; and at least one R⁶ is selected from the group consisting of—NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het, can be prepared byreplacing the R⁶ halo on the compound of formula (XVII) with an aminesubstituent selected from the group consisting of —NR⁷R⁸, —NR⁷Ay,—NHHet, —NHR¹⁰Ay and —NHR¹⁰Het. Methods for the conversion of compoundsof formula (XVII) to compounds of formula (I) are described above inconnection with the synthesis according to Scheme 2.

Compounds of formula (XVII) can be prepared by reacting a compound offormula (XX) with a compound of formula (X) followed by oxidativearomatization.

-   -   wherein all variables are as defined above in connection with        Scheme 3.

The condensation is conveniently carried out by treating the compound offormula (XX) with a compound of formula (X) in an inert solvent,optionally in the presence of a base. The reaction may be heated to50–150° C. or performed at ambient temperature. Suitable inert solventsinclude lower alcohols such as, for example, methanol, ethanol,isopropanol and the like. The base is typically sodium alkoxide,potassium carbonate, or an amine base such as triethylamine. In anotherembodiment, the solvent is N,N-dimethylformamide and the base ispotassium carbonate, or an amine base such as triethylamine. Thereaction produces a dihydropyrimidine intermediate.

Preferrably in the same reaction vessel, the dihydropyrimidineintermediate may be oxidized to a compound of formula (I) by theaddition of an oxidizing agent The reaction may be heated to 50–150° C.or performed at ambient temperature. Preferrably, the oxidizing agent isoxygen (O₂), palladium on carbon,2,3-dichloro-5,6dicyano-1,4-benzoquinone, or the like.

Compounds of formula (XX) may be conveniently prepared by oxidation ofcompounds of formula (XIX).

-   -   wherein all variables are as defined above in connection with        Scheme 3.

Preferred oxidizing agents for the oxidation of compounds of formula(XIX) include but are not limited to manganese dioxide, and the like.The oxidation is typically carried out in an inert solvent such as forexample, dichloromethane, chloroform, N,N-dimethylformamide, ether, andthe like.

Compounds of formula (XIX) may be conveniently prepared by reacting acompound of formula (XIII) with a compound of formula (XVIII).

-   -   wherein M¹ is a metal such as for example, lithium,        magnesium(II) halides, cerium(III) halides, and the like and all        other variables are as defined above in connection with        Scheme 3. Compounds of formula (XVIII) may be purchased from        commercial sources or prepared by methods known to one skilled        in the art. The compounds of formula (XIII) may be prepared        using the methods described above in connection with Scheme 2        above.

In addition to the foregoing process for preparing certain compounds offormula (I), the present invention also provides certain intermediatecompounds for use in the preparation of such compounds of formula (I)according to the foregoing process. Such intermediates are depicted inScheme 3 above.

In another embodiment, compounds of formula (I) wherein Y is N; and R²is selected from the group consisting of alkyl, cycloalkyl, alkenyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het, —S(O)_(n)R⁹,—S(O)_(n)Ay, —S(O)_(n)Het, —S(O)NR⁷R⁸, —NR⁷R⁸, —NH Het, —NHR¹⁰Het,—NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay, may be conveniently prepared by theprocess outlined in Scheme 3-A below.

wherein:

-   R¹ is H;-   R² is selected from the group consisting of halo, alkyl, cycloalkyl,    alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het,    —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸,    NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;    -   each R⁷ and R⁸ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —OR⁹, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹,        —C(S)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl,        —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,        —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R¹⁰,        —R¹⁰SO₂NR⁹R¹¹, —R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹ and —R¹⁰SO₂NHCOR⁹;    -   each R⁹ and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1–10, and        —R¹⁰NR¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl and alkynyl;    -   n is 0, 1 or 2;    -   Ay is aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;-   Y is N;-   R³ and R⁴ are the same or different and are each independently    selected from the group consisting of H, halo, alkyl, cycloalkyl,    alkenyl, Ay, Het, —OR⁷, —OAy, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay,    —SO₂NHR⁹, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Het, —R¹⁰OR⁷, —R¹⁰OAy,    —R¹⁰NR⁷R⁸ and R¹⁰NR⁷Ay;-   q is 0, 1, 2, 3, 4 or 5;-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, cycloalkyl, alkenyl,    cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —C(O)R⁹, —CO₂R⁹,    —C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)Het, —C(O)NHR¹⁰Het,    —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸,    —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het,    —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹,    —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,    —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano,    nitro and azido; or    -   two adjacent R⁵ groups together with the atoms to which they are        bonded form a C₅₋₆ cycloalkyl or aryl;-   p′ is 1, 2 or 3; and-   each R⁶ is the same or different and is independently selected from    the group consisting of halo, alkyl, cycloalkyl, alkenyl,    cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay,    —OR¹⁰Het, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁹, —C(O)Ay, —C(O)NR⁷Ay,    —C(O)NHR¹⁰Ay, —C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸,    —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸,    —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het,    —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹,    —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het, —R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸,    —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,    —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹,    —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or    -   two adjacent R⁶ groups together with the atoms to which they are        bonded form a C₅₋₆ cycloalkyl or a 5- or 6-membered heterocyclic        group containing 1 or 2 heteroatoms;-   R^(6x) is selected from the group consisting of —NR⁷R⁸ where R⁷ and    R⁸ are not both H, —NR⁷Ay, —NHHet, —NHR¹⁰Het and —NHR¹⁰Ay; and-   M¹ is Li, Mg-halide or cerium-halide, wherein halide is halo.

Generally, the process for preparing compounds of formula (I) wherein Yis N; and R² is selected from the group consisting of alkyl, cycloalkyl,alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het—S(O)_(n)R⁹,—S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het,—NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay, (all formulas and all other variableshaving been defined above in connection with Scheme 3-A), comprises thefollowing steps:

-   (a) reacting a 2-chloro-5-trifluoromethylpyridine of formula (XI-A)    with an acetophenone of formula (XXVII) to prepare a compound of    formula (III-A);-   (b) reacting the compound of formula (III-A) with a hydroxylamine    source to prepare a compound of formula (IV-A);-   (c) reacting the compound of formula (IV-A) with an acylating or    sulfonylating agent to prepare a compound of formula (V-A);-   (d) rearranging the compound of formula (V-A) to prepare a compound    of formula (VI-A);-   (e) formylating the compound of formula (VI-A) to prepare a compound    of formula (XIII-A);-   (f) reacting the compound of formula (XIII-A) with a compound of    formula (XVIII) to prepare a compound of formula (XIX-A);-   (g) oxidizing the compound of formula (XIX-A) to prepare a compound    of formula (XX-A);-   (h) reacting a compound of formula (XX-A) with a compound of    formula (X) followed by oxidative aromatization to prepare a    compound of formula (XXX);-   (i) reacting the compound of formula (XXX) with sodium ethoxide to    prepare a compound of formula (XXXI);-   (j) reacting the compound of formula (XXXI) with an acid, followed    by hydrolysis of the resulting ester to give a compound of formula    (XXXII);-   (k) reacting the compound of formula (XXXII) with diphenylphosphoryl    azide in tert-butanol to give a compound of formula (I-X);-   (l) optionally cleaving the compound of formula (I-X) to give a    compound of formula (I-Y); and-   (m) optionally converting the compound of formula (I-Y) to a    compound of formula (I-Z) using conditions selected from the group    consisting of cross coupling, reductive amination, alkylation,    acylation and sulfonylation.

More specifically, compounds of formula (I) wherein Y is N; and R² isselected from the group consisting of alkyl, cycloalkyl, alkenyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het—S(O)_(n)R⁹, —S(O)Ay,—S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het, —NHR¹⁰Ay,—R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay, can be prepared by converting a compound offormula (XXX) to a compound of formula (I) using the methods describedabove in connection with the process of Scheme 1-A.

Compounds of formula (XXX) can be prepared using methods analogous tothose described above for the preparation of compounds of formula (XVII)according to Scheme 3, with the exception that the first step (i.e., thepreparation of compounds of formula (III-A)) involves the condensationof 2-chloro-5-trifluoromethylpyridine with the acetophenone of formula(XXVII) under basic conditions, in place of the reaction of the picolineof formula (XI) with the benzoylating agent of formula (II) as isemployed in the synthesis of compounds of formula (VI) as described inScheme 1.

The compounds of formula (XXX) can be converted to compounds of formula(I) using the methods described above in connection with Scheme (1-A).

Compounds of formula (I), may be conveniently prepared by the processoutlined in Scheme 4 below.

wherein:

-   R¹ is H;-   R² is selected from the group consisting of halo, alkyl, cycloalkyl,    alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het,    —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸,    —NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;    -   each R⁷ and R⁸ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —OR⁹, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹,        —C(S)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl,        —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,        —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R¹⁰,        —R¹⁰SO₂NR⁹R¹¹, —R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹ and —R¹⁰SO₂NHCOR⁹;    -   each R⁹ and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1–10, and        —R¹⁰NR¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl and alkynyl;    -   n is 0, 1 or 2;    -   Ay is aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;-   Y is N or CH;-   R³ and R⁴ are the same or different and are each independently    selected from the group consisting of H, halo, alkyl, cycloalkyl,    alkenyl, Ay, Het, —OR⁷, —OAy, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay,    —SO₂NHR⁹, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Het, —R¹⁰OR⁷, —R¹⁰OAy,    —R¹⁰NR⁷R⁸ and R¹⁰NR⁷Ay;-   q is 0, 1, 2, 3, 4 or 5;-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, cycloalkyl, alkenyl,    cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —C(O)R⁹, —CO₂R⁹,    —C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)Het, —C(O)NHR¹⁰Het,    —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸,    —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het,    —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹,    —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,    —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano,    nitro and azido; or    -   two adjacent R⁵ groups together with the atoms to which they are        bonded form a C₅₋₆ cycloalkyl or aryl;-   p is 1, 2 or 3; and-   each R⁶ is the same or different and is independently selected from    the group consisting of halo, alkyl, cycloalkyl, alkenyl,    cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay,    —OR¹⁰Het, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁹, —C(O)Ay, —C(O)NR⁷Ay,    —C(O)NHR¹⁰Ay, —C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸,    —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸,    —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het,    —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹,    —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het, —R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸,    —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,    —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹,    —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or    -   two adjacent R⁶ groups together with the atoms to which they are        bonded form a C₅₋₆ cycloalkyl or a 5- or 6-membered heterocyclic        group containing 1 or 2 heteroatoms;-   wherein in the compounds of formula (VI), (XXII) and (XVII) at least    one R⁶ is selected from the group consisting of halo, —NR⁷R⁸,    —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; and-   wherein in the compounds of formula (I), at least one R⁶ is selected    from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NH R¹⁰Ay and    —NHR¹⁰Het;-   X¹ is chloro, bromo or iodo; and-   M² is —B(OH)₂, —B(ORa)₂, —B(Ra)₂, —Sn(Ra)₃, Zn-halide, ZnRa, or    Mg-halide where Ra is alkyl or cycloalkyl and halide is halo.

Generally, the process for preparing compounds of formula (I) (allformulas and variables having been defined above in connection withScheme 4), comprises the following steps:

-   (a) reacting a picoline of formula (XI) with a benzoylating agent of    formula (II) to prepare a compound of formula (III);-   (b) reacting the compound of formula (III) with a hydroxylamine    source to prepare a compound of formula (IV);-   (c) reacting the compound of formula (IV) with an acylating or    sulfonylating agent to prepare a compound of formula (V);-   (d) rearranging the compound of formula (V) to prepare a compound of    formula (VI);-   (e) halogenating a compound of formula (VI) to prepare a compound of    formula (XXII);-   (f) reacting a compound of formula (XXII) with a compound of    formula (XXIV) to prepare a compound of formula (XVII); and-   (g) in the embodiment wherein no R⁶ in the compound of    formula (XVII) is selected from the group consisting of —NR⁷R⁸,    —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het (i.e., R⁶ halo), replacing    the R⁶ halo of the compound of formula (XIII) with an amine    substituent selected from the group consisting of —NR⁷R⁸, —NR⁷Ay,    —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het to prepare a compound of formula (I).

More specifically, when no R⁶ is selected from the group consisting of—NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het (i.e., R⁶ halo),compounds of formula (I) can be prepared by replacing the R⁶ halo on thecompounds of formula (XVII) with an amine substituent selected from thegroup consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰HetMethods for the conversion of compounds of formula (XVII) to compoundsof formula (I) are described above in connection with the description ofScheme 2.

Compounds of formula (XVII) can be prepared by reacting a compound offormula (XXII) with a compound of formula (XXIV).

-   -   wherein all variables are as defined above in connection with        Scheme 4.

The reaction may be carried out in an inert solvent, in the presence ofa palladium (0) or nickel (0) catalyst The reaction may optionally beheated to about 50–150° C. Preferably the reaction is performed byreacting equimolar amounts of a compound of formula (XXII) with aHet-metal compound of formula (XXIV), but the reaction may also beperformed in the presence of an excess of compound of the formula(XXIV). The palladium or nickel catalyst is preferrably present in 1–10mol/compared to the compound of formula (XXII). Examples of suitablepalladium catalysts include but are not limited to,tetrakis(triphenylphosphine)palladium (0),dichlorobis(triphenylphosphine)palladium(II), tris(dibenzylideneacetone) dipalladium (0) and bis(diphenylphosphinoferrocene)palladium(II) dichloride. Suitable solvents include but are not limited to,N,N-dimethylformamide, toluene, tetrahydrofuran, dioxane, and1-methyl-2-pyrrolidinone. When the Het-metal compound of formula (XXIV)is an arylboronic acid or ester or an arylborinate the reaction is moreconveniently carried out by adding a base in a proportion equivalent to,or greater than, that of the compound of formula (XXIV). Het-metalcompounds of formula (XXIV) may be obtained from commercial sources orprepared either as discreet isolated compounds or generated in situusing methods known to one skilled in the art (Suzuki, A. J. OrganometChem. 1999, 576, 147; Stille, J. Angew. Chem. Int. Ed. Engl. 1986, 25,508; Snieckus, V. J. Org. Chem. 1995, 60, 292.)

Compounds of formula (XXII) can be prepared from compounds of formula(VI) by a halogenation procedure.

-   -   wherein all variables are as defined above in connection with        Scheme 4.

Typically, the halogenation reaction is carried out by subjecting thecompounds of formula (VI) to a halogenating agent in a suitable solvent.Suitable halogenating agents include but are not limited to,N-bromosuccinimide, trialkylammonium tribromides, bromine,N-chlorosuccinimide, N-iodosuccinimide, iodine monochloride, and thelike. Suitable solvents include, for example, N,N-dimethylformamide,tetrahydrofuran, dioxane, 1-methyl-2-pyrrolidinone, carbontetrachloride, toluene, dichloromethane, diethyl ether, and the like.

The compounds of formula (VI) may be prepared according to the methodsdescribed above in connection with Scheme 1.

In addition to the foregoing process for preparing compounds of formula(I), the present invention also provides certain intermediate compoundsfor use in the preparation of compounds of formula (I) according to theforegoing process. Such intermediates are depicted in Scheme 4 above.

In yet another embodiment of the present invention, compounds of formula(I) may be conveniently prepared by the process outlined in Scheme 4-Abelow.

wherein:

-   R¹ is H;-   R² is selected from the group consisting of halo, alkyl, cycloakyl,    alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het,    —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸,    —NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;    -   each R⁷ and R⁸ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —OR⁹, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹,        —C(S)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl,        —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,        —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R¹⁰,        —R¹⁰SO₂NR⁹R¹¹, —R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹ and —R¹⁰SO₂NHCOR⁹;    -   each R⁹ and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1–10, and        —R¹⁰NR¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl and alkynyl;    -   n is 0, 1 or 2;    -   Ay is aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;-   Y is N or CH;-   R³ and R⁴ are the same or different and are each independently    selected from the group consisting of H, halo, alkyl, cycloalkyl,    alkenyl, Ay, Het, —OR⁷, —OAy, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay,    —SO₂NHR⁹, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Het, —R¹⁰OR⁷, —R¹⁰OAy,    —R¹⁰NR⁷R⁸ and R¹⁰NR⁷Ay;-   q is 0, 1, 2, 3, 4 or 5;-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, cycloalkyl, alkenyl,    cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —C(O)R⁹, —CO₂R⁹,    —C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)Het, —C(O)NHR¹⁰Het,    —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸,    —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het,    —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹,    —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,    —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano,    nitro and azido; or    -   two adjacent R⁵ groups together with the atoms to which they are        bonded form a C₅₋₆ cycloalkyl or aryl;-   p′ is 0, 1 or 2; and-   each R⁶ is the same or different and is independently selected from    the group consisting of halo, alkyl, cycloalkyl, alkenyl,    cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay,    —OR¹⁰Het, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁹, —C(O)Ay, —C(O)NR⁷Ay,    —C(O)NHR¹⁰Ay, —C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸,    —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸,    —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het,    —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹,    —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het, —R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸,    —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,    —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹,    —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or    -   two adjacent R⁶ groups together with the atoms to which they are        bonded form a C₅₋₆cycloalkyl or a 5- or 6-membered heterocyclic        group containing 1 or 2 heteroatoms; —NHR¹⁰Het; and-   R^(6x) is selected from the group consisting of —NR⁷R⁸ wherein —R⁷    and —R⁸ are not both H, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het;-   X¹ is chloro, bromo or iodo; and-   M² is —B(OH)₂, —B(ORa)₂, —B(Ra)₂, —Sn(Ra)₃, Zn-halide, ZnRa, or    Mg-halide where Ra is alkyl or cycloalkyl and halide is halo.

Generally, the process for preparing compounds of formula (I) (allformulas and variables having been defined above in connection withScheme 4-A), comprises the following steps:

-   (a) reacting a 2-chloro-5-trifluoromethylpyridine of formula (XI-A)    with an acetophenone of formula (XXVII) to prepare a compound of    formula (III-A);-   (b) reacting the compound of formula (III-A) with a hydroxylamine    source to prepare a compound of formula (IV-A);-   (c) reacting the compound of formula (IV-A) with an acylating or    sulfonylating agent to prepare a compound of formula (V-A);-   (d) rearranging the compound of formula (V-A) to prepare a compound    of formula (VI-A);-   (e) halogenating a compound of formula (VI-A) to prepare a compound    of formula (XXII-A);-   (f) reacting a compound of formula (XXII-A) with a compound of    formula (XXIV) to prepare a compound of formula (XXX);-   (g) reacting the compound of formula (XXX) with sodium ethoxide to    prepare a compound of formula (XXXI);-   (h) reacting the compound of formula (XXXI) with an acid, followed    by hydrolysis of the resulting ester to give a compound of formula    (XXXII);-   (i) reacting the compound of formula (XXXII) with diphenylphosphoryl    azide in tert-butanol to give a compound of formula (I-X);-   (j) optionally cleaving the compound of formula (I-X) to give a    compound of formula (I-Y); and-   (k) optionally converting the compound of formula (I-Y) to a    compound of formula (I-Z) using conditions selected from the group    consisting of cross coupling, reductive amination, alkylation,    acylation and sulfonylation.

More specifically, compounds of formula (I) can be prepared byconverting the compounds of formula (XXX) to compounds of formula (I)using the methods described above in connection with the process ofScheme 1-A.

Compounds of formula (XXX) can be prepared using methods analogous tothose described above for the preparation of compounds of formula (XVII)according to Scheme 4, with the exception that the first step (i.e., thepreparation of compounds of formula (III-A)) involves the condensationof 2-chloro-5-trifluoromethylpyridine with the acetophenone of formula(XXVII) under basic conditions, in place of the reaction of the picolineof formula (XI) with the benzoylating agent of formula (II) as isemployed in the synthesis of compounds of formula (VI) as described inScheme 1. As will be apparent to those skilled in the art, a particularcompound of formula (I) may be converted to other compounds of formula(I) using techniques well known in the art. The foregoing synthesis ofSchemes 1-A, 2-A, 3-A and 4A demonstrate certain methods for convertinga compound of formula (I) to another compound of formula (I). Anothermethod of converting a compound of formula (I) to another compound offormula (I) comprises a) oxidizing the compound of formula (I-A) toprepare a compound of formula (I-B) and then b) optionally reacting acompound of formula (I-B) with an oxygen or amine nucleophile of formulaR², wherein R² is selected from the group consisting of —NR⁷R⁸, —OR⁷,—OAy, Het bonded through N, —NHHet, NHR¹⁰Het, OHet and —OR¹⁰Het toproduce a compound of formula I wherein R² is selected from the groupconsisting of —NR⁷R⁸, —OR⁷, —OAy, Het bonded through N, —NHHet,NHR¹⁰Het, OHet and —OR¹⁰Het.

wherein R² is selected from the group consisting of —NR⁷R⁸, —OR⁷, —OAy,Het bonded through N, —NHHet, NHR¹⁰Het, OHet and —OR¹⁰Het; p is 1, 2 or3; n′ is 1 or 2 and all other variables are as defined in connectionwith any of the processes described above.

More specifically, compounds of formula (I) can be prepared by reactinga compound of formula (I-B) (i.e., compounds of formula I wherein R² isS(O)_(n′)R⁹ where n′ is 1 or 2) with an oxygen or amine nucleophile offormula R², wherein R² is selected from the group consisting of —NR⁷R⁸,—OR⁷, —OAy, Het bonded through N, —NHHet, NHR¹⁰Het, OHet and —OR¹⁰Het.The reaction may be carried out neat or in a suitable solvent and may beheated to 50–150° C. Typically the solvent is a lower alcohol such asmethanol, ethanol, isopropanol and the like or solvent such asN,N-dimethylformamide or tetrahydrofuran, and the like. Optionally abase may be used to facilitate the reaction. Typically the base can bepotassium carbonate, or an amine base such as triethylamine.

Compounds of formula (I-B) may be conveniently prepared by reacting acompound of formula (I-A) (i.e., compounds of formula (I) wherein R² is—S(O)_(n)R⁹ where n is 0) with an oxidizing agent in an inert solvent,optionally in the presence of a base.

Typically the oxidizing agent is a peracid such as m-chloroperbenzoicacid or the like optionally with a base such as sodium bicarbonate.Careful monitoring of the stoichiometry between the oxidizing agent andthe substrate allows the product distribution between sulfoxide (n=1),and sulfone (n=2) to be controlled. Suitable solvents include but arenot limited to, dichloromethane, chloroform and the like.

Compounds of formula (I-A) are prepared by methods described abovewherein R² is —SR⁹ from the reaction of compounds selected from thegroup consisting of compounds of formula (XVI), compounds of formula(IX) and compounds of formula (XX) with a compound of formula (X-A)(i.e., the compound of formula (X) wherein R² is —SR⁹). The requisitecompound of formula (X-A) can be obtained from commercial sources orprepared by methods known to one skilled in the art.

Another particularly useful method for converting a compound of formula(I) to another compound of formula (I) comprises reacting a compound offormula (I-C) (i.e., a compound of formula (I) wherein R² is fluoro)with an amine (including substituted amines, heterocycles andheteroaryls, particularly those linked through N), and optionallyheating the mixture to 50–150° C. to prepare a compound of formula (I-D)(i.e., a compound of formula (I) wherein R² is selected from the groupconsisting of —NR⁷R⁸, Het, —NHHet and —NHR¹⁰Het).

wherein all other variables are as defined in connection with any of theprocesses described above.

This procedure may be carried out by mixing a compound of formula (I-C)in an amine neat, or in a suitable solvent with an excess of amine toproduce a compound of formula (I-D). Typically the solvent is a loweralcohol such as methanol, ethanol, isopropanol and the like. Othersuitable solvents may include N,N-dimethylformamide,1-methyl-2-pyrrolidine and the like.

As a further example, a compound of formula (I-E) (i.e., a compound offormula (I) wherein q is 1 or more and at least one R⁵ is O-methyl) maybe converted to a compound of formula (I-F) (i.e., a compound of formula(I) wherein q is 1 or more and at least one R⁵ is OH) using conventionaldemethylation techniques. Additionally, a compound of formula (I-F) mayoptionally be converted to a compound of formula (I-G) (i.e., a compoundof formula (I) wherein q is 1 or more and at least one R⁵ is OR¹⁰). Forexample, the foregoing conversions are represented schematically asfollows:

wherein q′ is 0, 1, 2, 3 or 4; Me is methyl, and all other variables areas defined in connection with any of the processes described above.

The demethylation reaction may be carried out by treating a compound offormula (I-E) in a suitable solvent with a Lewis acid at a temperatureof −78° C. to room temperature, to produce a compound of formula (I-F).Typically the solvent is an inert solvent such as dichloromethane,chloroform, acetonitrile, toluene and the like. The Lewis acid may beboron tribromide, trimethylsilyl iodide or the like.

Optionally, a compound of formula (I-F) may be further converted to acompound of formula (l-G) by an alkylation reaction. The alkylationreaction may be carried out by treating a compound of formula (I-F) insuitable solvent with an alkyl halide of formula R¹⁰-Halo where R¹⁰ isas defined above, to form a compound of formula (I-G). The reaction ispreferably carried out in the presence of a base and with optionallyheating to 50–200° C. The reaction may be carried out in solvents suchas N,N-dimethylformamide, dimethylsulfoxide and the like. Typically thebase is potassium carbonate, cesium carbonate, sodium hydride or thelike. Additionally, as will be apparent to one skilled in the art, thealkylation reaction can be carried out under Mitsunobu conditions.

As a further example of methods for converting a compound of formula (I)to another compound of formula (I), a compound of formula (I-H) (i.e., acompound of formula (I) wherein q is 1 or more and at least one R⁵ ishalo) may be converted to a compound of formula (I-J) (i.e., a compoundof formula (I) wherein q is 1 or more and at least one R⁵ is Het) or acompound of formula (I-K) (i.e., a compound of formula (I) wherein q is1 or more and at least one R⁵ is Ay). For example, the conversion of acompound of formula (I-H) to a compound of formula (I-J) or a compoundof formula (I-K) is shown schematically below.

wherein q′ is 0 1, 2, 3 or 4; M⁴ is selected from the group consistingof —B(OH)₂, —B(ORa)₂, —B(Ra)₂, and —Sn(Ra)₂ wherein Ra is alkyl orcycloalkyl; and all other variables are as defined in connection withany of the processes described above.

The conversion of a compound of formula (I-H) to a compound of formula(I-J) or (I-K) is carried out by coupling the compound of formula (I-H)with a compound of formula Het-M⁴ to make a compound of formula (I-J) ora compound of formula Ay-M⁴ to make a compound of formula (I-K). Thereaction may be carried out in an inert solvent, in the presence of apalladium (0) source. The reaction may optionally be heated to 50–150°C. Preferably the reaction is performed by reacting equimolar amounts ofa compound of formula (I-H) with a compound of formula Het-M⁴ or Ay-M⁴(depending upon whether a compound of formula (I-J) or a compound offormula (I-K) are desired). The reaction may also be performed in thepresence of an excess Het-M⁴ or Ay-M⁴. The palladium (0) catalyst ispreferrably present in 1–25 mol % compared to the compound of formula(I-H). Examples of suitable palladium catalysts include but are notlimited to, tetrakis(triphenylphosphine)palladium (0),dichlorobis(triphenyl-phosphine)palladium(II), andbis(diphenylphosphinoferrocene)palladium (II) dichloride. Suitablesolvents include but are not limited to, N,N-dimethylformamide, toluene,tetrahydrofuran, dioxane, and 1-methyl-2-pyrrolidinone. When thecompound of formula Het-M⁴ or Ay-M⁴ is a boronic acid or ester or aborinate the reaction is more conveniently carried out by adding a basein a proportion equivalent to, or greater than, that of the compound offormula Het-M⁴ or Ay-M⁴. Compounds of formula Het-M⁴ and Ay-M⁴ may beobtained from commercial sources or prepared either as discreet isolatedcompounds or generated in situ using methods known to one skilled in theart. (Suzuki, A. J. Organomet Chem. 1999, 576, 147; Stille, J. Angew.Chem. Int. Ed. Engl. 1986, 25, 508; Snieckus, V. J. Org. Chem. 1995, 60,292.)

In yet another example, a compound of formula (I-H) (i.e., a compound offormula (I) wherein q is 1 or more and at least one R⁵ is halo) isconverted to a compound of formula (I-L) (i.e., a compound of formula(I) wherein q is 1 or more and at least one R⁵ is NH₂). Optionally, acompound of formula (I-L) may then be converted to a compound of formula(I-M) (i.e., a compound of formula (I) wherein q is 1 or more and atleast one R⁵ is —NR⁷R⁸). For example, the foregoing conversions arerepresented schematically as follows:

wherein q′ is 0, 1, 2, 3 or 4, and all other variables are as defined inconnection with any of the processes described above, with the provisothat in compounds of formula (I-M) both R⁷ and R⁸ of the amine attachedto the 2-phenyl are not H.

The process of converting a compound of formula (1-H) to a compound offormula (I-L) is carried out by reacting a compound of formula (I-H)with an imine in the presence of a palladium (0) source, a base and asuitable ligand, followed by hydrolysis to give a compound of formula(I-L). See J. Wolfe, et al., Tetrahedron Letters 38:6367–6370 (1997).Typically the imine is benzophenoneimine, the palladium (0) source istris(dibenzylideneacetone)dipalladium(0), the base is sodiumtert-butoxide and the ligand isracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl. Suitable solventsinclude N,N-dimethylformamide and the like.

Reaction of a compound of formula (I-L) with a compound of formulaR⁷-halogen in a suitable'solvent in the presence of base, optionallywith heating may be used to prepare a compound of formula (I-M).Typically the base is triethylamine or pyridine and the solventN,N-dimethylformamide and the like. Transformations well known to thoseskilled in the art for use with anilines can be used to convert thecompounds of formula (I-L) to compounds of formula (I-M).

Additional compounds of formula (I-M) can be obtained by reductiveamination of compounds of formula (I-L) with ketones or aldehydes. See,A. Abdel-Magid, et al., J. Org. Chem. 61:3849–3862 (1996). Typically acompound of formula (I-L) is treated with an aldehyde or a ketone in thepresence of an acid, such as acetic acid, and a reducing agent, such assodium triacetoxyborohydride and the like, in an inert solvent such asdichloroethane and the like.

Based on this disclosure and the examples contained herein one skilledin the art can readily convert compounds of formula (I) or apharmaceutically acceptable salt, solvate or physiologically functionalderivative thereof into other compounds of formula (I), or apharmacetuically acceptable salt, solvate or physiologically functionalderivative thereof.

The present invention also provides radiolabeled compounds of formula(I) and biotinylated compounds of formula (I). Radiolabeled compounds offormula (I) and biotinylated compounds of formula (I) can be preparedusing conventional techniques. For example, radiolabeled compounds offormula (I) can be prepared by reacting the compound of formula (I) withtritium gas in the presence of an appropriate catalyst to produceradiolabeled compounds of formula (I).

In one preferred embodiment, the compounds of formula (I) are tritiated.

The radiolabeled compounds of formula (I) and biotinylated compounds offormula (I) are useful in assays for the identification of compounds forthe treatment or prophylaxis of viral infections such as herpes viralinfections. Accordingly, the present invention provides an assay methodfor identifying compounds which have activity for the treatment orprophylaxis of viral infections such as herpes viral infections, whichmethod comprises the step of specifically binding the radiolabeledcompound of formula (I) or the biotinylated compound of formula (I) tothe target protein. More specifically, suitable assay methods willinclude competition binding assays. The radiolabeled compounds offormula (I) and biotinylated compounds of formula (I) can be employed inassays according to the methods conventional in the art.

The following examples are intended for illustration only and are notintended to limit the scope of the invention in any way. Reagents arecommercially available or are prepared according to procedures in theliterature. Example numbers refer to those compounds listed in thetables above. ¹H and ¹³C NMR spectra were obtained on Varian Unity PlusNMR spectrophotometers at 300 or 400 MHz, and 75 or 100 MHzrespectively. ¹⁹F NMR were recorded at 282 MHz. Mass spectra wereobtained on Micromass Platform, or ZMD mass spectrometers from MicromassLtd. Altrincham, UK, using either Atmospheric Chemical Ionization (APCI)or Electrospray Ionization (ESI). Analytical thin layer chromatographywas used to verify the purity of some intermediates which could not beisolated or which were too unstable for full characterization, and tofollow the progress of reactions. Unless otherwise stated, this was doneusing silica gel (Merck Silica Gel 60 F254). Unless otherwise stated,column chromatography for the purification of some compounds, used MerckSilica gel 60 (230–400 mesh), and the stated solvent system underpressure. All compounds were characterized as their free-base formunless otherwise stated. On occasion the corresponding hydrochloridesalts were formed to generate solids where noted.

EXAMPLE 14-[5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine

a) 2-(4-Chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone

To a cold (020 C.) solution of 4-chloro-2-picoline (5.0 g, 39 mmol) andethyl 4-fluorobenzoate (6.6 g, 39 mmol) in tetrahydrofuran (100 mL) wasadded lithium bis(trimethylsilyl)amide (80 mL, 1.0 M in tetrahydrofuran,80 mmol) dropwise via a pressure equalizing funnel over 30 minutes. Uponcomplete addition, the cold bath was removed and the resulting solutionwas stirred at room temperature for 15 hours. The reaction mixture wasconcentrated under reduced pressure and methanol was added to thereaction, resulting in the formation of a white precipitate. Theprecipitate was collected by filtration and dried to give2-(4-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone (9.6 g, 99%) as awhite solid. ¹H-NMR (DMSO-d₆): δ 7.90 (m, 3H), 7.11 (t, 2H), 6.56 (s,1H), 5.67 (s, 1H), 4.14 (m, 2H); ¹⁹F-NMR (DMSO-d₆): δ −115.67; MS m/z250 (M+1).

b) 2-(4-Chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone oxime

To a solution of 2-(4-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone(9.6 g, 38 mmol) in methanol (200 mL) was added hydroxylaminehydrochloride (13.5 g, 190 mmol) followed by the addition of a sodiumhydroxide solution (7.8 g, 190 mmol in 50 mL of water). The resultingsuspension was heated at reflux for 2 hours and then allowed to cool toroom temperature. The mixture was concentrated and water was added tothe resulting slurry. A white precipitate formed, which was collected byfiltration, washed with water and dried (magnesium sulfate) to give2-(4-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone oxime (8.45 g, 84%)as a white solid. ¹H-NMR (DMSO-d₆): δ 11.56 (s, 1H), 8.44 (d, 1H), 7.80(m, 2H), 7.40 (m, 2H), 7.22 (m, 2H), 4.29 (s, 2H); ¹⁹F-NMR (DMSO-d₆): δ−113.44; MS m/265 (M+1).

c) 5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine

To a solution of 2-(4-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanoneoxime (8.0 g, 30 mmol) in 1,2-dimethoxyethane (50 mL) at 0° C. was addedtrifluoroacetic anhydride (6.3 g, 30 mmol), keeping the temperaturebelow 10° C. during the addition. After the addition was complete, thereaction was warmed to room temperature. The solution was then cooled to4° C. and a solution of triethylamine (8.4 mL, 60 mmol) in1,2-dimethoxyethane (20 mL) was added over a period of 0.5 hours. Themixture was allowed to warm to room temperature and was stirred for 1.5hours. To this mixture was added iron(II) chloride (40 mg) and thereaction was heated at 75° C. for 15 hours.

The reaction mixture was poured into water (300 mL). The resultingsuspension was extracted with ethyl acetate. The combined organics weredried (magnesium sulfate), filtered and concentrated to a solid residue.This residue was purified by flash chromatography (1:1 ethylacetate-hexane) to give5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine (4.2 g, 57%) as awhite solid. ¹H-NMR (CDCl₃): δ 8.36 (d, 1H), 7.93 (q, 2H), 7.49 (d, 1H),7.15 (t, 2H), 6.70 (dd, 1H), 6.69 (s, 1H); ¹⁹F-NMR (CDCl₃): δ −113.30;MS m/z 247 (M+1).

d) 5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine-3-carbaldehyde

Phosphorous oxychloride (0.6 mL, 6.4 mmol) was added toN,N-dimethylformamide (10 mL) and the resulting mixture stirred at roomtemperature for 10 minutes.5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine (1.0 g, 4.1 mmol) wasadded and the reaction mixture was stirred at room temperature for 12hours. The reaction mixture was poured into ice-water and neutralized topH 7 with aquous ammonium hydroxide. The resulting slurry was extractedwith dichloromethane (3×40 mL). The combined organics were washed withbrine, dried (magnesium sulfate), filtered and concentrated to give,after recrystallization from acetonitrile,5-chloro-2-(4-fluorophenyl)pyrazolo [1,5-α]pyridine-3-carbaldehyde (0.95g, 85%) as a white solid. ¹H-NMR (CDCl₃): δ10.07 (s, 1H), 8.49 (d, 1H),8.44 (d, 1H), 7.78 (q, 2H), 7.22 (t, 2H), 7.07 (dd, 1H); MS m/z 275(M+1).

e)1-[5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-butyn-1-one

To a solution of5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine-3-carbaldehyde (0.93g, 3.4 mmol) in tetrahydrofuran (20 mL) at −78° C. was addedethynylmagnesium bromide (16 mL, 0.5 M in tetrahydrofuran, 8.0 mmol).The mixture was allowed to warm to room temperature and stirred for 1hour. Water was added to the reaction and the resulting mixture wasextracted with ethyl acetate. The ethyl acetate phase was dried(magnesium sulfate), filtered and concentrated to a solid residue. Thisresidue was dissolved in dichloromethane (50 mL) and manganese dioxide(5 g) was added. This slurry was stirred at room temperature for 2hours. The manganese dioxide was removed by filtration and the filtratewas concentrated to a solid. This solid was purified by flashchromatography (dichloromethane) to give1-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-butyn-1-one(0.63 g, 62% for two steps) as a white solid. ¹H-NMR (CDCl₃): δ 8.52 (d,1H), 8.47 (d, 1H), 7.69 (q, 2H), 7.18 (t, 2H), 7.07 (dd, 1H), 3.00 (s,1H); ¹⁹F-NMR (CDCl₃): δ −111.69; MS m/z 299 (M+1).

f)4-[5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine

To a solution of1-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-butyn-1-one(0.61 g. 2.0 mmol) in N,N-dimethylformamide was added cyclopentylguanidine hydrochloride (0.67 g, 4.1 mmol) followed by anhydrouspotassium carbonate (0.57 g, 4.1 mmol). The resulting mixture was heatedat 80° C. for 12 hours. Upon cooling to room temperature, water wasadded. The mixture was extracted with ethyl acetate. The ethyl acetatephase was washed with brine, dried (magnesium sulfate), filtered andconcentrated in vacuo. The resulting residue was purified by flashchromatography (1:1 ethyl acetate-hexane) to give, afterrecrystallization from acetonitrile,4-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(0.6 g, 74%) as a white solid. ¹H-NMR (CDCl₃): δ8.54 (broad s, 1H), 8.40(d, 1H), 8.04 (d, 1H), 7.60 (q, 2H), 7.16 (t, 2H), 6.88 (dd, 1H), 6.28(d, 1H), 5.22 (d, 1H), 4.40 (m, 1H), 1.4–2.2 (m, 8H); ¹⁹F-NMR (CDCl₃): δ−112.5; MS m/z 408 (M+1).

EXAMPLE 2N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine

To a solution of4-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(0.1 g, 0.25 mmol) in cyclopentylamine (5 mL) was addedracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (46 mg, 0.08 mmol),cesium carbonate (120 mg, 0.38 mmol) and palladium (II) acetate (11 mg,0.05 mmol).

The resulting mixture was stirred at 80° C. for 24 hours, at which timethe reaction was judged complete by thin layer chromatography. Thesolution was cooled to room temperature and ethyl acetate and water wereadded to the reaction mixture. The phases were separated, and the aquousphase again extracted with ethyl acetate. The combined organics weredried (magnesium sulfate), filtered and concentrated. The resultingresidue was purified by flash chromatography (1:1 hexanes-ethyl acetate)to giveN-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine(78 mg, 70%) as a white solid. ¹H-NMR (CDCl₃): δ 8.16 (d, 1H), 7.95 (d,1H), 7.58 (q, 2H), 7.38 (d, 1H), 7.12 (t, 2H), 6.24 (dd, 1H), 6.20 (d,1H), 5.05 (d, 1H), 4.40 (m, 1H), 4.13 (m, 1H), 3.89 (m, 1H), 1.5–2.2 (m,16H); ¹⁹F-NMR (CDCl₃): δ −113.7; MS m/z 457 (M+1).

EXAMPLE 33-[2-(Cyclopentylamino)-4-pyrimidinyl]2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine

To a solution of4-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(0.1 g, 0.25 mmol) in toluene (5 mL) was added benzophenone imine (0.13g, 0.75 mmol), tris(dibenzylideneacetone)dipalladium (0.02 g, 0.03mmol), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.05 g, 0.09mmol) and sodium tert-butoxide (0.07 g, 0.75 mmol). The reaction washeated at 100° C. for 3 hours, then allowed to cool to room temperature.Aqueous sodium bicarbonate and ethyl acetate were added to the reactionmixture. The phases were separated and the organic phase was washed withbrine and dried (magnesium sulfate). Filtration and concentration,followed by purification by flash chromatography (1:4 ethylacetate-hexanes to 1:1 ethyl acetate-hexanes) gave3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-(diphenylmethylene)-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amineas a solid. This solid was dissolved in tetrahydrofuran (10 mL). To thissolution at 0° C. was added 4N hydrochloric acid (2 mL) dropwise.Subsequently, the reaction mixture was stirred for 30 minutes. Thereaction mixture was diluted with ethyl acetate, then saturated aquousbicarbonate was added slowly until the ethyl acetate layer turned clear.The resulting mixture was stirred for 30 minutes. The organic phase waswashed with water, brine and dried (magnesium sulfate). Filtration andconcentration, followed by flash chromatography (ethyl acetate) gave3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine(54 mg, 57%) as a yellow foam. ¹H-NMR (CDCl₃): δ 8.22 (d, 1H), 7.97 (d,1H), 7.58 (q, 2H), 7.11 (t, 2H), 6.34 (dd, 1H), 6.20 (d, 1H), 5.14 (d,1H), 4.31 (m, 1H), 4.10 (m, 3H), 1.5–2.2 (m, 8H); ¹⁹F-NMR (CDCl₃): δ−113.4; MS m/z 389 (M+1).

EXAMPLE 4N-[3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-yl]methanesulfonamide

To a solution of3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine(60 mg, 0.15 mmol) in anhydrous pyridine (5 mL) was added methylsulfonylchloride (36 mg, 0.3 mmol). The reaction was stirred at room temperatureovernight. The reaction mixture was diluted with ethyl acetate, thensaturated aquous bicarbonate was added. The phases were separated, theorganic phase was washed with water, brine and dried (magnesiumsulfate). Filtration and concentration, followed by flash chromatography(1:1 ethyl acetate-hexane) gaveN-[3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-yl]methanesulfonamide(35 mg, 50%) as a solid. ¹H-NMR (CDCl₃): δ 8.42 (d, 1H), 8.15 (d, 1H),8.05 (d, 1H), 7.60 (q, 2H), 7.13 (t, 2H), 6.90 (dd, 1H), 6.30 (d, 1H),5.34 (d, 1H), 4.30 (m, 1H), 3.12 (s, 3H), 1.5–2.2 (m, 8H); ¹⁹F-NMR(CDCl₃): δ −112.64; MS m/z 467 (M+1).

EXAMPLE 53-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-6-amine

a) 1-(4-Fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)ethanone

To a solution of 4-fluoroacetophenone (13.8 g, 0.100 mol) and2-chloro-5-trifluoromethylpyridine (20.0 g, 0.110 mol) intetrahydrofuran (400 mL) was added sodium hydride (950%, 5.56 g, 0.220mol) in several portions. The reaction was stirred at room temperaturefor 72 hours then carefully quenched by the addition of water (300 mL)and diethyl ether (200 mL). The organic layer was separated andextracted with 6N HCl (2×300 mL). The aqueous extracts were cooled to 0°C. and 6N NaOH was used to adjust the solution to pH12. The mixture wasthen extracted with diethyl ether and the combined organic extracts weredried over magnesium sulfate. The drying agent was removed by filtrationand the filtrate was evaporated to dryness to afford the title compoundas a tautomeric mixture, 20.9 g (73%). ¹H NMR (CDCl₃): δ 8.87(s),8.63(s), 8.14(dd, J=5.1, 8.4 Hz), 8.00–7.83(m), 7.51(d, J=8.4 Hz),7.22–7.12(m), 6.13(s), 4.60(s). MS (ES): 284 (M+1).

b) 1-(4-Fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)ethanone oxime

To a solution of1-(4-fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)ethanone (80.0 g,0.282 mol) in methanol (1 L) at room temperature was added 10% aqueoussodium hydroxide (436 mL, 1.09 mol). The resulting solution was stirredvigorously as solid hydroxylamine hydrochloride (98.0 g, 1.40 mol) wasadded. The mixture was heated to reflux for 2 hours, treated withdecolorizing charcoal while hot, then filtered through Celite while hotThe filtrate was concentrated to one-half its original volume and thencooled to 0° C. with stirring for one hour. The resulting solids werecollected by filtration, washed with water, and dried under vacuum at50° C. overnight to provide the title compound as a light yellow powder,73.9 g (88%). ¹H NMR (DMSO-d₆): δ 11.60(s, 1H), 8.86(s, 1H), 8.14(dd,1H, J=2.1, 8.1 Hz), 7.78(dd, 2H, J=5.7, 9.0 Hz), 7.53(d, 1H, J=8.4 Hz),7.23(t, 2H, J=9.0 Hz), 4.40(s, 2H). MS (ES): 299 (M+1).

c) 3-(4-Fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)-2H-azirine

To a solution of1-(4-fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)ethanone oxime (25.0g, 0.084 mol) in methylene chloride (400 mL) was added triethylamine(46.7 mL, 0.335 mol). The solution was cooled to 0° C. under a nitrogenatmosphere, and trifluoroacetic anhydride (14.1 mL, 0.100 mol) was addeddropwise. The reaction was stirred for 0.5 hours then quenched withwater. The organic layer was separated and dried over anhydrousmagnesium sulfate. The drying agent was removed by filtration and thesolvent was evaporated from the filtrate to leave an oil. The residuewas loaded onto a silica gel column and eluted with 15% ethyl acetate inhexanes to give the title compound as an oil which solidified onstanding, 19.4 g (82%). ¹H NMR (CDCl₃): δ 8.76(s, 1H), 7.93(dd, 2H,J=5.4, 8.7 Hz), 7.83(dd, 1H, J=2.1, 8.4 Hz), 7.27(t, 2H, J=8.7 Hz), 7.21(d, 1H, J=8.1 Hz), 3.54 (s, 1H). MS (ES): 281 (M+1).

d) 2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridine

3-(4-Fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)-2H-azirine (40.0 g,0.143 mol) was dissolved in 1,2,4-trichlorobenzene (400 mL) and themixture was heated to 200° C. for 10 hours. The reaction mixture wasthen cooled to room temperature and poured onto a silica gel column. Thecolumn was eluted with hexanes to remove the 1,2,4-trichlorobenzene, andthen with 20% diethyl ether in hexanes to elute the product. The desiredfractions were combined and the solvent was evaporated under reducedpressure to leave the title compound, 28.7 g (710%). ¹H NMR (CDCl₃): δ8.84(s, 1H), 7.98(dd, 2H, J=5.4, 8.7 Hz), 7.65(d, 1H, J=9.3 Hz), 7.28(d,1H, J=9.3Hz), 7.20(t, 2H, J=8.7 Hz), 6.88(s, 1H). MS (ES): 281 (M+1).

e)2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridine-3-carbaldehyde

To a cold (0° C.) solution of phosphorus oxychloride (8.0 mL 86 mmol) inN,N-dimethylformamide (160 mL) was added2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridine (11.0 g,39.3 mmol). The reaction mixture was stirred at room temperature for 72hours, then quenched with ice water. The solid precipitate was collectedon a filter to provide2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridine-3-carbaldehyde(11.4 g, 94%) as a white solid. R_(f) 0.45 (4:1 hexanes:ethyl acetate);¹H NMR (400 MHz, CDCl₃): δ 10.15 (s, 1H), 8.92 (s, 1H), 8.53 (d, 1H),7.80 (m, 2H), 7.70 (d, 1H), 7.27 (t, 2H); ¹⁹F NMR (CDCl₃) δ −62.62,−110.62; MS m/z 307 (M−1).

f)1-[2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-ol

To a cold (−78° C.) suspension of2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridine-3-carbaldehyde(11.4 g, 37.0 mmol) in tetrahydrofuran (100 mL) was addedethynylmagnesium bromide (111 mL, 0.5 M in tetrahydrofuran, 56 mmol).The reaction mixture was warmed to room temperature and stirred for 14hours. The reaction mixture was poured into water and adjusted toneutral pH with 1N aqueous hydrochloric acid. The aqueous mixture wasextracted with ethyl acetate. The combined extracts were washed withwater and brine. The organic layer was dried over magnesium sulfate.Filtration and concentration provided 1-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-ol (11.9 g,96%) as a tan solid. R_(f) 0.18 (4:1 hexanes:ethyl acetate); ¹H NMR (300MHz, CDCl₃) δ 8.81 (s, 1H), 8.15 (d, 1H), 7.75 (m, 2H), 7.35 (d, 1H),7.19 (t, 2H), 5.76 (s, 1H), 2.71 (d, 1H), 2.60 (d, 1H); MS m/z 335(M+1).

g)1-[2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-one

To a cold (0° C.) solution of1-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-ol(5.00 g, 15.0 mmol) in chloroform (400 mL) was added manganese dioxide(130 g, 1.50 mol). The reaction mixture was stirred at 0° C. for 1.5hours. The reaction mixture was filtered through a pad of Celite. Thefiltrate was concentrated in vacuo to provide1-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-one(3.44 g, 690/%) as a clear oil. R_(f) 0.39 (4:1 hexanes:ethyl acetate);¹H NMR (400 MHz, CDCl₃) δ 8.90 (s, 1H), 8.61 (d, 1H), 7.72–7.69 (m, 3H),7.17 (m, 2H), 3.06 (s, 1H); MS m/333 (M+1).

h)N-Cyclopentyl-4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinamine

To a suspension of N-cyclopentylguanidine hydrochloride (2.20 g, 13.5mmol) in ethanol (70 mL) was added sodium ethoxide (4.5 mL, 3 M inethanol, 14 mmol). The mixture was stirred at room temperature for 30minutes, then cooled to 0° C. To this mixture was added1-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-one(3.44 g, 10.4 mmol) portionwise. The reaction mixture was stirred at 0°C. for 30 minutes, followed by room temperature for 15 hours. Thereaction mixture was diluted with water (400 mL). The solid precipitatewas collected on a filter to provideN-cyclopentyl-4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinamide(4.48 g, 98%) as an orange solid. ¹H NMR (400 MHz, CDCl₃) δ 8.84 (s,1H), 8.51 (d, 1H), 8.11 (d, 1H), 7.64 (dd, 2H), 7.44 (dd, 1H), 7.17 (t,2H), 6.33 (d, 1H), 5.17 (d, 1H), 4.34 (m, 1H), 2.15–2.06 (m, 2H),1.84–1.52 (m, 6H); ¹⁹F NMR (CDCl₃): δ −62.70, −112.25 MS m/z 442 (M+1);mp 155–156° C.

i)N-Cyclopentyl-4-[2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinamide

To a dry round bottom flask was added sodium metal (1.9 g, 83 mmol).Ethanol (110 mL) was added and allowed to react with sodium at roomtemperature until completely dissolved.N-Cyclopentyl-4-[2-(4-fluorophenyl)-6-(trifluoromethyl)-pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinamide(4.48 g, 10.1 mmol) was added and the reaction mixture was stirred at60° C. for 18 hours. The reaction mixture was cooled and concentrated invacuo to approximately one-fourth of the original volume. The resultingmixture was diluted with water and extracted with ethyl acetate. Theorganic layer was washed with water and brine, then dried over magnesiumsulfate. Filtration and concentration providedN-cyclopentyl-4-[2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinamide (4.86 g, 92%) as an off-white solid. R_(f) 0.15(4:1 hexanes:ethyl acetate); ¹H NMR (300 MHz, CDCl₁₃) δ 8.81 (s, 1H),8.39 (d, 1H), 8.06 (d, 1H), 7.62 (m, 2H), 7.47 (d, 1H), 7.14 (t, 2H),6.32 (d, 1H), 5.12 (d, 1H), 4.35 (m, 1H), 3.43 (q, 6H), 2.08 (m, 2H),1.80–1.51 (m, 6H), 1.21 (t, 9H); MS m/z 520 (M+1).

j) Ethyl3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine-6-carboxylate

To a solution ofN-cyclopentyl-4-[2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo-[1,5-α]pyridin-3-yl]-2-pyrimidinamide(1.0 g, 1.9 mmol) in acetone (40 mL) and water (10 mL) was addedp-toluenesulfonic acid monohydrate (915 mg, 4.81 mmol). The reactionmixture was stirred at room temperature for 2 hours. The pH of thereaction mixture was adjusted to slightly basic using saturated aqueoussodium bicarbonate solution. The reaction mixture was concentrated invacuo to one third of the original volume, then diluted with water. Theprecipitate was collected on a filter to provide ethyl3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine-6-carboxylate(722 mg, 85%) as an orange solid. R_(f) 0.15 (4:1 hexanes:ethylacetate); ¹H NMR (300 MHz, CDCl₃) δ 9.22 (s, 1H), 8.38 (d, 1H), 8.08(br, 1H), 7.85 (d, 1H), 7.64 (m, 2H), 7.16 (t, 2H), 6.34 (s, 1H), 5.26(br, 1H), 4.44 (q, 2H), 4.35 (br, 1H), 2.08 (m, 2H), 1.80–1.52 (m, 6H),1.43 (t, 3H); MS m/z 446 (M+1).

k)3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine-6-carboxylicacid hydrochloride

To a solution of ethyl3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine-6-carboxylate(385 mg, 0.864 mmol) in dioxane (9 mL) and water (1 mL) was addedlithium hydroxide monohydrate (109 mg, 2.60 mmol). The reaction mixturewas heated at 95° C. for 5 hours. The reaction mixture was concentratedin vacuo. A suspension of the concentrated residue in water wasacidified with 1 N aqueous hydrochloric acid. The solid precipitate wascollected on a filter to provide3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-pyrazolo[1,5-α]pyridine-6-carboxylicacid hydrochloride (359 mg, 92%) as an orange solid. ¹H NMR (400 MHz,DMSO-d₆) δ 9.27 (s, 1H), 8.73 (br, 1H), 8.46 (br, 1H), 8.12 (br, 1H),7.97 (br, 1H), 7.67 (m, 2H), 7.36 (t, 2H), 6.35 (br, 1H), 4.18 (br, 1H),1.95 (br, 2H), 1.71 (br, 2H), 1.56 (br, 4H); MS m/z 418 (M+1).

l) tert-Butyl3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-pyrazolo[1,5-α]pyridin-6-ylcarbamate

To a suspension of3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-pyrazolo[1,5-α]pyridine-6-carboxylicacid hydrochloride (60 mg, 0.13 mmol) in tertbutanol was addedtriethylamine (39 μL, 0.28 mmol) and diphenylphosphoryl azide (34 μL,0.16 mmol). The reaction mixture was heated at reflux for 2.5 hours. Thereaction mixture was cooled to room temperature and diluted with ethylacetate. The organic layer was washed with 5% aqueous citric acidsolution, water, saturated aqueous sodium bicarbonate solution, andbrine. The organic layer was dried over sodium sulfate. Filtration andconcentration followed by flash chromatography (39:1dichloromethane:methanol) provided tert-butyl3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-6-ylcarbamate(35 mg, 540/%) as a light green oil. R_(f) 0.32 (29:1dichloromethane:methanol); ¹H NMR (400 MHz, CDCl₃) δ 8.95 (br, 1H), 8.35(d, 1H), 8.01 (br, 1H), 7.60 (m, 2H), 7.19 (d, 1H), 7.12 (t, 2H), 6.51(s, 1H), 6.31 (d, 1H), 4.34 (m, 1H), 2.07 (m, 2H), 1.90–1.52 (m, 6H),1.53 (s, 9H); MS m/z 489 (M+1).

m)3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-6-aminedihydrochloride

To a solution of tert-butyl3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-6-ylcarbamate(35 mg, 0.072 mmol) in dichloromethane was addedhydrogen chloride (144μL, 4 N in dioxane, 0.58 mmol). The reaction mixture was stirred at roomtemperature for 18 hours. The reaction mixture was diluted with etherand the precipitated solids were collected on a filter to provide3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-6-aminedihydrochloride (9 mg, 27%) as a brownish yellow solid. ¹H NMR (300 MHz,DMSO-d₆) δ 8.25 (br, 1H), 7.97–7.91 (m, 2H), 7.53 (m, 2H), 7.26 (t, 2H),7.06 (d, 1H), 6.15 (br, 1H), 4.14–3.85 (br, 1H), 1.85 (br, 2H), 1.65(br, 2H), 1.48 (br, 4H); MS m/z 389 (M+1).

EXAMPLE 6N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-6-amine.

To a suspension of3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-6-aminedihydrochloride (90 mg, 0.20 mmol) in 1,2-dichloroethane was addedcyclopentanone (26 μL, 0.29 mmol), acetic acid (56 μL, 0.98), and sodiumtriacetoxyborohydride (82 mg, 0.39 mmol). The reaction mixture wasstirred at room temperature 16 hours then quenched with water. Theresultant mixture was diluted with ethyl acetate and saturated aqueoussodium bicarbonate solution. The organic layer was separated and washedwith water and brine. The organic layer was dried over magnesiumsulfate. Filtration and concentration followed by flash chromatography(4:1 hexanes:ethyl acetate to 7:3 hexanes:ethyl acetate) providedN-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-6-amine(40 mg, 45%) as a green oil. R_(f) 0.25 (2:1 hexanes:ethyl acetate); ¹HNMR (300 MHz, CDCl₃) δ 8.25 (d, 1H), 8.00 (d, 1H), 7.79 (s, 1H), 7.61(m, 2H), 7.13 (t, 2H), 6.86 (d, 1H), 6.32 (d, 1H), 5.23 (br, 1H), 4.36(m, 1H), 3.72 (m, 1H), 3.54 (d, 1H), 2.14–2.02 (m, 4H), 1.81–1.51 (m,12H); MS m/z 457 (M+1). To a solution of the product in ether was added1 M HCl in ether. The precipitated solid was isolated to give thecorresponding HCl salt.

EXAMPLE 73-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-isopropylpyrazolo[1,5-α]pyridin-6-amine.

In a similar manner as described in Example 6 from3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]-6-aminedihydrochloride (40 mg, 0.087 mmol) and acetone was obtained3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-isopropylpyrazolo[1,5-α]-6-amine(16 mg, 43%) as a pale green solid. R_(f) 0.21 (2:1 hexanes:EtOAc); ¹HNMR (400 MHz, CD₃OD) δ 8.25 (d, 1H), 7.89 (d, 1H), 7.72 (s, 1H), 7.56(m, 2H), 7.19 (d, 2H), 7.03 (d, 1H), 6.24 (d, 1H), 4.22 (m, 1H), 3.52(m, 1H), 2.00 (m, 2H), 1.78–1.51 (m, 6H), 1.24 (d, 6H); MS m/z 431 M+1).

EXAMPLE 83-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-(2-methoxyethyl)pyrazolo[1,5-α]pyridin-5-amine.

4-[5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(0.1 g, 0.25 mmol) and 2-methoxyethylamine were treated withrac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, cesium carbonate andpalladium (II) acetate as described in Example 2 to give, afterpurification by flash chromatography (1:1 hexanes-ethyl acetate),3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-(2-methoxyethyl)pyrazolo[1,5-α]pyridin-5-amine(65 mg, 59%) as a solid. ¹H-NMR (CDCl₃): δ 8.2 (d, 1H), 7.9 (d, 1H),7.55 (m, 2H), 7.4 (m, 1H), 7.1 (t, 2H), 6.32 (dd, 1H), 6.2 (d, 1H), 5.3(broad s, 1H), 4.54 (t, 1H), 4.4 (m, 1H), 3.65 (m, 2H), 3.4 (s, 3H),3.35 (m, 2H), 2.1 (m, 2H), 1.5–1.8 (m, 6H); ¹⁹F-NMR (CDCl₃): δ −113.46;MS m/z 447 (M+1).

EXAMPLE 93-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-isopropylpyrazolo[1,5-α]pyridin-5-amine.

4-[5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(0.1 g, 0.25 mmol) and isopropylamine were treated withrac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, cesium carbonate andpalladium (II) acetate as described in Example 2 to give, afterpurification by flash chromatography (1:1 hexanes-ethyl acetate),3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-isopropylpyrazolo[1,5-α]pyridin-5-amine(70 mg, 66%) as a solid. ¹H-NMR (CDCl₃): δ 8.17 (d, 1H), 7.9 (d, 1H),7.58 (q, 2H), 7.4 (m, 1H), 7.15 (t, 2H), 6.24 (dd, 1H), 6.2 (d, 1H),5.25 (broad s, 1H), 4.4 (m, 1H), 3.95 (d, 1H), 3.75 (m, 1H), 2.1 (m,2H), 1.5–1.8 (m, 6H), 1.30 (d, 6H); ¹⁹F-NMR (CDCl₃): δ −113.45; MS m/z431 (M+1).

EXAMPLE 10N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-pyrazolo[1,5-α]pyridin-5-amine.

a) 2-(4-Chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone

To a cold (0° C.) solution of 4-chloro-2-picoline (10 g, 78.4 mmol) andethyl 4-methoxybenzoate (14.1 g, 78.4 mmol) in tetrahydrofuran (100 mL)was added lithium bis(trimethylsilyl)amide (157 mL, 1.0 M intetrahydrofuran, 157 mmol) dropwise via a pressure equalizing funnelover half an hour. Upon complete addition, the ice bath was removed andthe resulting solution was heated at 45° C. for 15 hours. The mixturewas cooled to room temperature, and the solution was concentrated.Methanol was added to quench the reaction, resulting in the formation ofa yellow precipitate. The precipitate was collected by filtration anddried to give the product as a mixture of enol and ketone tautomers. MSm/z 262 (M+1).

b) 2-(4-Chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone oxime

To a solution of 2-(4-chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone inmethanol (200 mL) was added hydroxylamine hydrochloride (27.2 g, 392mmol) followed by the addition of a sodium hydroxide solution (15.7 g,392 mmol in 50 mL of water). The resulting suspension was heated atreflux for 1 hour and then allowed to cool to room temperature. Themixture was concentrated and water was added to the resulting slurry. Awhite precipitate formed, which was collected by filtration, washed withwater and dried to give2-(4-chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone oxime (11.8 g) as awhite solid. ¹H NMR (CDCl₃): δ 8.47 (d, 1H), 7.72 (d, 2H), 7.36 (d, 1H),7.19 (dd, 1H), 6.91 (d, 2H), 4.43 (s, 2H), 3.84 (s, 3H); MS m/z 277(M+1).

c) 5-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridine

To a solution of 2-(4-chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanoneoxime (11.8 g, 42.6 mmol) in 1,2-dimethoxyethane (200 mL) at 0° C. wasadded trifluoroacetic anhydride (6.3 mL, 44.8 mmol), keeping thetemperature below 10° C. during the addition. After the addition wascomplete, the reaction was warmed to 15° C. The solution was then cooledto 4° C. and a solution of triethylamine (12.5 mL, 89.5 mmol) in1,2-dimethoxyethane (15 mL) was added over a period of 0.5 hours. Themixture was allowed to warm to room temperature and was stirred at roomtemperature for 5 hours. To this mixture was added iron(II)chloride(0.11 g, 0.85 mmol) and the reaction was heated at 75° C. for 15 hours.The reaction mixture was poured into water (300 mL). The resultingsuspension was extracted with ethyl acetate. The organic phase was dried(magnesium sulfate), filtered and concentrated to a solid. This solidwas recrystallized from methanol to give5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridine (6.64 g, 60%) aswhite needles. ¹H NMR (CDCl₃): δ 8.35 (d, 1H), 7.86 (d, 2H), 7.46 (d,1H), 6.97 (d, 2H), 6.67 (d, 1H), 6.65 (s, 1H), 3.85 (s, 3H); MS m/z 259(M+1).

d) 1-[5-(Chloro)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]ethanone

To a solution of 5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridine(3.0 g, 11.6 mmol) in toluene (100 mL) at room temperature was addedacetic anhydride (1.6 mL, 17.4 mmol). Boron trifluoride diethyletherate(1.8 mL, 13.9 mmol) was then added dropwise and the resulting solutionwas heated at reflux for 4 hours. The reaction mixture was cooled toroom temperature and quenched by the dropwise addition of saturatedaqueous sodium bicarbonate. The reaction was extracted with ethylacetate, and the ethyl acetate phase washed with brine, dried (magnesiumsulfate), filtered and concentrated. The residue was purified byrecrystallization from ethyl acetate-hexanes to give1-[5-(chloro)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]ethanone(2.31 g, 66%). ¹H NMR (CDCl₃): δ 8.44 (d, 1H), 8.40 (d, 1H), 7.49 (d,2H), 7.02 (d, 2H), 6.97 (dd, 1H), 3.85 (s, 3H), 2.15 (s, 3H); MS m/z 301(M+1).

e)1-[5-(Cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]ethanone

To a solution of1-[5-(chloro)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]ethanone(1.77 g, 5.88 mmol) in toluene (60 mL) was added successivelyracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (220 mg, 0.35 mmol),cesium carbonate (2.88 g, 8.83 mmol), cyclopentylamine (2.9 mL, 29.4mmol), and palladium (II) acetate (53 mg, 0.24 mmol). The resultingmixture was stirred at 95° C. for 3 days, at which time the reaction wasjudged complete by thin layer chromatography. The solution was cooled toroom temperature and diethyl ether and water were added to the reactionmixture. The phases were separated, and the aqueous phase againextracted with diethyl ether. The combined organic phases were dried(magnesium sulfate), filtered and concentrated. The resulting residuewas purified by flash chromatography (3:2 hexanes:ethyl acetate) to give1-[5-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]ethanone(1.14 g, 56%) as a yellow solid. ¹H NMR (CDCl₃): δ 8.19 (d, 1H), 7.52(d, 2H), 7.45 (d, 1H), 7.03 (d, 2H), 6.35 (dd, 1H), 4.15 (broad s, 1H),3.98 (m, 1H), 3.91 (s, 3H), 2.21–2.15 (m, 2H), 2.11 (s, 3H), 1.79–1.54(m, 6H); MS m/z 350 (M+1).

f)1-[5-(Cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one

A solution of1-[5-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3yl]ethanone(1.14 g, 3.26 mmol) in N,N-dimethylformamide dimethyl acetal (25 mL) washeated at reflux for 5 days. The mixture was allowed to cool to roomtemperature. Water was added and the resulting mixture was extractedwith ethyl acetate. The organic phase was dried (magnesium sulfate),filtered and concentrated. The resulting residue was crystallized fromethyl acetate to give1-[5-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one(1.05 g, 80%) as a yellow solid. ¹H NMR (CDCl₃): δ 8.11 (d, 1H), 7.56(m, 3H), 7.41 (d, 1H), 6.95 (d, 2H), 6.22 (dd, 1H), 5.07 (d, 1H), 4.11(d, 1H), 3.95 (m, 1H), 3.84 (s, 3H), 3.0–2.3 (broad, 6H), 2.12 (m, 2H),1.74–1.48 (m, 6H); MS m/z 405 (M+1).

g)N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-pyrazolo[1,5-α]pyridin-5-amine

To a solution of1-[5-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one(1.05 g, 2.60 mmol) in N,N-dimethylformamide (20 mL) was addedN-cyclopentyl guanidine hydrochloride (1.27 g, 7.79 mmol; Prepared bymodification of a procedure from Bannard, R. A. B. et al., Can. J. Chem.1958, 36,1541–1549), followed by potassium carbonate (0.54 g, 3.89mmol). The resulting solution was heated at reflux for 15 hours. Uponcooling to room temperature, water was added. The mixture was extractedwith ethyl acetate. The ethyl acetate phase was washed with brine, dried(magnesium sulfate), filtered and concentrated in vacuo. The resultingresidue was purified by flash chromatography (4:6 ethyl acetate:hexane)to giveN-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-pyrazolo[1,5-α]pyridin-5-amine(1.06 g, 87%) as a yellow solid. ¹H NMR (CDCl₃): δ 8.15 (d, 1H), 7.91(d, 1H), 7.51 (d, 2H), 7.41 (d, 1H), 6.94 (d, 2H), 6.26 (d, 1H), 6.22(dd, 1H). 5.11 (d, 1H), 4.42 (m, 1H), 4.09 (d, 1H), 3.88 (m, 1H), 3.85(s, 3H), 2.10–2.01 (m, 4H), 1.76–1.52 (m, 12H); MS m/z 469 (M+1).

EXAMPLE 114-[5-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine

a) 5-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridine-3-carbaldehyde

To N,N-dimethylformamide (20 mL) at 0° C. was added phosphorousoxychloride (0.54 mL, 7.8 mmol). After the addition was complete, themixture was warmed to room temperature and stirred for 1 hour. To thiswas added5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridine[1,5-α]pyridine (1.0g, 3.86 mmol) and the resultant solution was stirred 2 hours. Water wasadded, followed by dichloromethane. The aqueous layer was extracted withdichloromethane. The combined organics were washed with brine, driedover magnesium sulfate, filtered and concentrated. A white crystallinecompound,5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridine-3-carbaldehyde (0.9g, 81%), was obtained. ¹H NMR (CDCl₃): δ 10.12 (s, 1H), 8.52 (d, 1H),8.47 (d, 1H), 7.76 (d, 2H), 7.11–7.06 (m, 3H), 3.93 (s, 3H); MS m/z 287(M+1).

b)1-[5-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-ol

To a cold (-78° C.) suspension of5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridine-3-carbaldehyde (0.90g, 3.14 mmol) in tetrahydrofuran (50 mL) was added ethynylmagnesiumbromide (7.5 mL, 0.5 M in tetrahydrofuran, 3.77 mmol) dropwise. Thereaction mixture was stirred at −78° C. for 1 hour, then at roomtemperature for 4 hours. The resultant solution was poured intosaturated aqueous sodium bicarbonate and extracted with ethyl acetate.The organic layer was washed with water and brine and the combinedorganics were dried over magnesium sulfate. Filtration and concentrationprovided1-[5-chloro-2-(4methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-ol(1.05 g, 100%) as a white solid. ¹H NMR (CDCl₃) δ 8.40 (d, 1H), 8.05 (s,1H), 7.72 (d, 2H), 7.05 (d, 2H), 6.80 (dd, 1H), 5.78 (s, 1H), 3.91 (s,3H), 2.74 (s, 1H), 2.53 (s, 1H); MS m/z 313 (M+1).

c)1-[5-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1one

To a solution of1-[5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-ol(1.05 g, 3.14 mmol) in chloroform (100 mL) was added manganese dioxide(6.82 g, 78.5 mmol). The reaction mixture was stirred at roomtemperature for 3.5 hours. The suspension was filtered through a pad ofCelite and the filtrate was concentrated to give1-[5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-one(0.99 g, 100%o) as a pale yellow solid. ¹H NMR (CDCl₃) δ 8.50 (d, 1H),8.46 (d, 1H), 7.64 (d, 2H), 7.04 (dd, 1H), 6.98 (d, 2H), 3.87 (s, 3H),2.99 (s, 1H); MS m/z 295 (M+1).

d)4-[5-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine.

Sodium ethylate (0.7 mL (2.09 mmol), 210% in ethanol) and cyclopentylguanidine hydrochloride (0.47 g, 2.88 mmol) were added sequentially toethanol (30 mL). The resulting solution was stirred at room temperaturefor 30 minutes.1-[5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-one(0.5 g, 1.61 mmol) was added, and the suspension was stirred at roomtemperature for 2 days. The reaction was quenched by the addition ofwater. The aqueous phase was extracted by ethyl acetate. The organicswere combined, washed with brine and dried over magnesium sulfate.Filtration and concentration gave a solid. This solid was recrystallizedfrom methanol to give4-[5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(0.45 g, 66%) as a pale yellow solid. ¹H NMR (CDCl₃) δ 8.59 (b, 1H),8.42 (d, 1H), 8.05 (d, 1H), 7.59 (d, 2H), 7.03 (d, 2H), 6.91 (dd, 1H),6.39 (d, 1H), 5.34 (broad s, 1H), 4.42 (m, 1H), 3.92 (s, 3H), 2.17 (m,2H), 1.86–1.60 (m, 6H); MS m/z 420 (M+1).

EXAMPLE 123-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-isopropyl-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine

To a solution of4-[5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(100 mg, 0.24 mmol) in cyclopentylamine (50 mL) was added successivelyracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (71 mg, 0.11 mmol),cesium carbonate (155 mg, 0.48 mmol) and palladium (II) acetate (16 mg,0.07 mmol). The resultant mixture was heated to 95° C. for 2 days atwhich time the reaction was judged complete by thin layerchromatography. The solution was cooled to room temperature and ethylacetate was added. The organic layer was washed with water and brine.The aqueous layer was extracted with ethyl acetate and the combinedorganics dried over magnesium sulfate. Filtration and concentration,followed by flash chromatography (3:2 hexanes:ethyl acetate) provided3-[2-(cyclopentylamino)-4-pyrimidinyl]N-isopropyl-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine(62 mg, 58%) as a yellow solid. ¹H NMR (CDCl₃) δ 8.13 (d, 1H), 7.91 (d,1H), 7.50 (d, 2H), 7.44 (d, 1H), 6.93 (d, 2H), 6.25 (d, 1H), 6.19 (dd,1H), 5.25 (d, 1H), 4.41 (m, 1H), 4.05 (d, 1H), 3.83 (s, 3H), 3.69 (m,1H), 2.08–2.02 (m, 2H), 1.71–1.48 (m, 6H), 1.23 (d, 6H); MS m/z 443(M+1).

EXAMPLE 134Bromo-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine

N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo-[1,5-α]pyridin-5-amine(100 mg, 0.22 mmol) was dissolved in dichloromethane (5 mL) and treatedwith N-bromosuccinimide (40 mg, 0.22 mmol). The reaction mixture wasstirred for 10 minutes. Additional dichloromethane and 1N aqueous sodiumhydroxide was added. The phases were separated, the organic phase washedwith water, dried (magnesium sulfate), filtered and concentrated todryness to give 100 mg of the title compound as a yellow foam. ¹H NMR(CDCl₃): δ 8.32 (d, 1H), 8.22 (d, 1H), 7.53 (q, 2H), 7.04 (t, 2H), 6.53(m, 2H), 5.17 (d, 1H), 4.72 (d, 1H), 4.33 (m, 1H), 3.95 (m, 1H), 2.1–1.4(m, 16H); ¹⁹F NMR (CDCl₃): δ −113.97; MS m/z 536 (M+1).

EXAMPLE 144-Chloro-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine

The title compound was synthesized in a similar manner as describedabove. ¹H NMR (CDCl₃): δ 8.30 (d, 1H), 8.22 (d, 1H), 7.54 (q, 2H), 7.05(t, 2H), 6.53 (m, 2H), 5.14 (d, 1H), 4.62 (d, 1H), 4.32 (m, 1H), 3.97(m, 1H), 2.1–1.4 (m, 16H); ¹⁹F NMR (CDCl₃): δ −113.99; MS m/z 492 (M+1).

EXAMPLE 154-Bromo-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine

The title compound was synthesized in a similar manner as describedabove. ¹H NMR (CDCl₃): δ 8.32 (d, 1H), 8.20 (d, 1H), 7.48 (d, 2H), 6.87(d, 2H), 6.54 (d, 1H), 6.49 (d, 1H), 5.20 (d, 1H), 4.70 (d, 1H), 4.35(m, 1H), 3.95 (m, 1H), 3.83 (s, 3H), 2.1–1.4 (m, 16H); MS m/z 549 (M+1).

EXAMPLE 164-Chloro-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine

The title compound was synthesized in a similar manner as describedabove. ¹H NMR (CDCl₃): δ 8.30 (d, 1H), 8.20 (d, 1H), 7.48 (d, 2H), 6.88(d, 2H), 6.54 (d, 1H), 6.52 (d, 1H), 5.17 (d, 1H), 4.60 (d, 1H), 4.32(m, 1H), 3.97 (m, 1H), 3.84 (s, 3H), 2.1–1.4 (m, 16H); MS m/z 504 (M+1).

EXAMPLE 17N-Butyl-3-[2-(butylamino)pyridin-4-yl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-4-amine

The title compound was made in a similar manner as described above. ¹HNMR (CDCl₃): δ 8.01 (m, 2H), 7.50 (m, 2H), 7.35 (m, 1H), 7.06 (m, 2H),6.78 (t, 1H), 6.66 (d, 1H), 6.46 (s, 1H), 6.17 (d, 1H), 5.93 (bs, 1H),3.20 (m, 2H), 3.14 (m, 2H), 1.56 (m, 4H), 1.42 (m, 2H), 1.32 (m, 2H),0.94 (M, 6H); MS m/z 432 (M+1).

EXAMPLE 184-{5-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-α]pyridin-2-yl}phenol

Treatment ofN-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine(500 mg, 1.07 mmol) in dichloromethane with boron tribromide, followedby aqueous workup, gave4-{5-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-α]pyridin-2-yl}phenol(390 mg, 81%) as a yellow solid. ¹H NMR (CD₃OD) δ 8.16 (d, 1H), 7.85 (d,1H), 7.40 (m, 3H), 6.90 (d, 2H), 6.53 (dd, 1H), 6.27 (d, 1H), 4.44 (m,1H), 3.92 (m, 1H), 2.11 (m, 4H), 1.84–1.58 (m, 12H). MS m/z 455 (M+1).

EXAMPLE 19N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-isobutoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine

Treatment of4-{5-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-α]pyridin-2-yl}phenol(100 mg, 0.22 mmol) in N,N-dimethylformamide (5 mL) with isobutylbromide and potassium carbonate gaveN-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-isobutoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine(83 mg, 740/%) as a pale yellow solid. ¹H NMR (CDCl₃) δ 8.14 (d, 1H),7.92 (d, 1H), 7.49 (d, 2H), 7.41 (d, 1H), 6.93 (d, 2H), 6.27 (d, 1H),6.20 (dd, 1H), 5.10 (d, 1H), 4.41 (m, 1H), 4.13 (d, 1H), 3.87 (m, 1H),3.76 (d, 2H), 2.05 (m, 5H), 1.76–1.52 (m, 12H), 1.02 (d, 6H). MS m/z 511(M+1).

EXAMPLE 20N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[4-(cyclopropylmethoxy)phenyl]pyrazolo[1,5-α]pyridin-5-amine

In a similar manner described above from4-{5-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-α]pyridin-2-yl}phenol(100 mg, 0.22 mmol) was obtainedN-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[4-(cyclopropylmethoxy)phenyl]pyrazolo[1,5-α]pyridin-5-amine(69 mg, 62%) as a yellow solid. ¹H NMR (CDCl₃) δ 8.11 (d, 1H), 7.91 (d,1H), 7.48 (d, 2H), 7.41 (d, 1H), 6.92 (d, 2H), 6.25 (d, 1H), 6.19 (dd,1H), 5.18 (bs, 1H), 4.40 (m, 1H), 4.19 (bs, 1H), 3.83 (m, 3H), 2.04 (m,4H), 1.70–1.49 (m, 12H), 1.25 (m, 1H), 0.63 (m, 2H), 0.35 (m, 2H). MSm/z 509 (M+1).

EXAMPLE 21 Biological Activity

In the following example, “MEM” means Minimal Essential Media; “FBS”means Fetal Bovine Serum; “NP40” and “Igepal” are detergents; “MOI”means Multiplicity of Infection; “NaOH” means sodium hydroxide; “MgC₂”means magnesium chloride; “dATP” means deoxyadenosine 5′ triphosphate;“dUTP” means deoxyuridine 5′ triphosphate; “dCTP” means dexoxycytidine5′ triphosphate; “dGTP” means deoxyguanosine 5′ triphosphate; “GuSCN”means Guanidinium thiocyanate; “EDTA” means ethylenediamine tetraaceticacid; “TE” means Tris-EDTA; “SCC” means sodium chloride/sodium citrate;“APE” means a solution of ammonia acetate, ammonia phosphate, EDTA;“PBS” means phosphate buffered saline; and “HRP” means horseradishperoxidase.

a) Tissue Culture and HSV Infection

Vero 76 cells were maintained in MEM with Earle's salts, L-glutamine, 8%FBS (Hyclone, A-1111-L) and 100 units/mL Penicillin-100 μg/mLStreptomycin. For assay conditions, FBS was reduced to 2%. Cells areseeded into 96-well tissue culture plates at a density of 5×10⁴cells/well after being incubated for 45 min at 37° C. in the presence ofHSV-1 or HSV-2 (MOI=0.001). Test compounds are added to the wells andthe plates are incubated at 37° C. for 40–48 hours. Cell lysates areprepared as follows: media was removed and replaced with 150 μL/well 0.2N NaOH with 1% Igepal CA 630 or NP-40. Plates were incubated up to 14days at room temperature in a humidified chamber to prevent evaporation.

(b) Preparation of Detection DNA

For the detection probe, a gel-purified, digoxigenin-labeled, 710-bp PCRfragment of the HSV UL-15 sequence was utilized. PCR conditions included0.5 μM primers, 180 μM dTTP, 20 μM dUTP-digoxigenin (Boehringer Mannheim1558706), 200 μM each of dATP, dCTP, and dGTP_(,) 1×PCR Buffer II(Perkin Elmer), 2.5 mM MgCl₂, 0.025 units/μL of AmpliTaq Gold polymerase(Perkin Elmer), and 5 ng of gel-purified HSV DNA per 100 μL Extensionconditions were 10 min at 95° C., followed by 30 cycles of 95° C. for 1min, 55° C. for 30 sec. and 72° C. for 2 min. The amplification wascompleted with a 10-min incubation at 72° C. Primers were selected toamplify a 728 bp probe spanning a section of the HSV1 UL15 open readingframe (nucleotides 249–977). Single-stranded transcripts were purifiedwith Promega M13 Wizard kits. The final product was mixed 1:1 with amixture of 6 M GuSCN, 100 mM EDTA and 200 μg/mL herring sperm DNA andstored at 4° C.

(c) Preparation of Capture Plates

The capture DNA plasmid (HSV UL13 region in pUC) was linearized bycutting with Xba I, denatured for 15 min at 95° C. and dilutedimmediately into Reacti-Bind DNA Coating Solution (Pierce, 17250,diluted 1:1 with TE buffer, pH 8) at 1 ng/μL 75 μL/well were added toCorning (#3922 or 9690) white 96-well plates and incubated at roomtemperature for at least 4 hrs before washing twice with 300 μL/well0.2×SSC/0.05% Tween-20 (SSC/T buffer). The plates were then incubatedovernight at room temperature with 150 μL/well 0.2 N NaOH, 1% IGEPAL and10 μg/mL herring sperm DNA.

(d) Hybridization

Twenty-seven (27) μL of lysate was combined with 45 μL of hybridizationsolution (final concentration: 3M GuSCN, 50 mM EDTA, 100 μg/ml salmonsperm DNA, 5×Denhardt's solution, 0.25×APE, and 5 ng of thedigoxigenin-labeled detection probe). APE is 1.5 M NH₄-acetate, 0.15 MNH₄H₂ phosphate, and 5 mM EDTA adjusted to pH 6.0 Mineral oil (50 μL)was added to prevent evaporation. The hybridization plates wereincubated at 95° C. for 10 minutes to denature the DNA, then incubatedat 42° C. overnight. The wells were washed 6× with 300 μl/well SSC/Tbuffer then incubated with 75 μL/well anti-digoxigenin-HRP-conjugatedantibody (Boehringer Mannheim 1207733, 1:5000 in TE) for 30 min at roomtemperature. The wells were washed 6× with 300 μL/well with PBS/0.05%Tween-20 before 75 μL/well SuperSignal LBA substrate (Pierce) was added.The plates were incubated at room temperature for 30 minutes andchemiluminescence was measured in a Wallac Victor reader.

Results

The following results were obtained for HSV-1.

Example No. IC₅₀ (μM)  2 0.5  3 5  4 2  5 0.24  6 1  7 1.2  8 1  9 2.910 0.2 12 0.8 13 3.0  14. 1.9 15 3.5 16 2.8 17 2.5 18 1.2 19 0.5 20 0.3

The results demonstrate that the compounds of the present invention areuseful for the treatment and prophylaxis of herpes viral infections.

1. A compound of formula (I):

wherein: R¹ is H; R² is selected from the group consisting of halo,alkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet,—OR¹⁰Het, —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸,—NR⁷R⁸, —NHHet, —NHR¹⁰Het, —NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; each R⁷and R⁸ are the same or different and are independently selected from thegroup consisting of H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, —OR⁹,—C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂R¹⁰,—SO₂NR⁹R¹¹, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,—R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹,—R¹⁰SO₂R¹⁰, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰NHSO₂R⁹, R¹⁰NHCOR⁹ and —R¹⁰SO₂NHCOR⁹;each R⁹ and R¹¹ are the same or different and are independently selectedfrom the group consisting of H, alkyl, cycloalkyl, —R¹⁰cycloalkyl,—R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1–10, and —R¹⁰NR¹⁰R¹⁰; each R¹⁰ is thesame or different and is independently selected from the groupconsisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl and alkynyl; n is0, 1 or 2; Ay is aryl; Het is a 5- or 6-membered heterocyclic orheteroaryl group; Y is N; R³ and R⁴ are the same or different and areeach independently selected from the group consisting of H, halo, alkyl,cycloalkyl, alkenyl, Ay, Het, —OR⁷, —OAy, —C(O)R⁷, —C(O)Ay, —CO₂R⁷,—CO₂Ay, —SO₂NHR⁹, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Het, —R¹⁰OR⁷, —R¹⁰OAy,—R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; q is 0, 1, 2, 3, 4 or 5; each R⁵ is the same ordifferent and is independently selected from the group consisting ofhalo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, Ay, Het, —OR⁷,—OAy, —OHet, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)Het,—C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹,—S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het,—R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,—R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹,—R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or twoadjacent R⁵ groups together with the atoms to which they are bonded forma C₅₋₆ cycloalkyl or aryl; p is 1, 2 or 3; and each R⁶ is the same ordifferent and is independently selected from the group consisting ofhalo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, Ay, Het, —OR⁷,—OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)Ay,—C(O)NR⁷Ay, —C(O)NHR¹⁰Ay, —C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹,—C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het,—S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het,—R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹, —R¹⁰—O—C(O)Ay,—R¹⁰—O—C(O)Het, —R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹,—R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,—R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano, nitroand azido; or two adjacent R⁶ groups together with the atoms to whichthey are bonded form a C₅₋₆cycloalkyl or a 5- or 6-membered heterocyclicgroup containing 1 or 2 heteroatoms; wherein at least one R⁶ is selectedfrom the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and—NHR¹⁰Het; and or a pharmaceutically acceptable salt thereof.
 2. Thecompound according to claim 1 wherein R² is selected from the groupconsisting of Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het —S(O)_(n)R⁹,—S(O)_(n)Ay, —NR⁷R⁸, —NHHet, —NHR¹⁰Het, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay.
 3. Thecompound according to claim 1 wherein R² is —NR⁷R⁸.
 4. The compoundaccording to claim 1 wherein R³ and R⁴ are the same or different and areeach independently selected from the group consisting of H, halo, alkyl,—OR⁷, —CO₂R⁷ and—NR⁷R⁸.
 5. The compound according to claim 1 -wherein R³and R⁴ are each H.
 6. The compound according to claim 1 wherein q is 0,1 or
 2. 7. The compound according to claim 1 wherein each R⁵ is the sameor different and is independently selected from the group consisting ofhalo, alkyl, alkenyl, Ay, Het, —OR⁷, —CO₂R⁹, —C(O)NR⁷R⁸, —S(O)₂NR⁷R⁸,—NR⁷R⁸, —NHR¹⁰Ay, cyano, nitro and azido.
 8. The compound according toclaim 1, wherein each R⁵ is the same or different and is independentlyselected from the group consisting of halo, alkyl, —OR⁷ and cyano. 9.The compound according to claim 1 wherein p is 1 or
 2. 10. The compoundaccording to claim 1 -wherein p is
 1. 11. The compound according toclaim 1 -wherein p is 1 and R⁶ is at the C-5 position.
 12. The compoundaccording to claim 1 wherein p is 1 and R⁶ is at the C-6 position. 13.The compound according to claim 1 wherein each R⁶ is the same ordifferent and is independently selected from the group consisting ofhalo, alkyl, Ay, Het, —OR⁷, —OAy, —OHet, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay,—NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Het, —NHR¹⁰Ay and cyano.
 14. The compoundaccording to claim 1 wherein each R⁶ is the same or different and isindependently selected from the group consisting of halo, —NR⁷R⁸,—NR⁷Ay, —NHHet, —NHR¹⁰Het and —NHR¹⁰Ay.
 15. A compound selected from thegroup consisting of:N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo-[1,5-α]pyridin-5-amine;3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine;N-[3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4fluorophenyl)pyrazolo[1,5-α]pyridin-5yl]methanesulfonamide;3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-6-amine;N-Cyclopentyl;-3-[2-(cyclopentylamino)-4-pyrimidinyl]2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-6-amine;3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-isopropylpyrazolo[1,5-α]pyridin-6-amine;3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-(2-methoxyethyl)pyrazolo[1,5-α]pyridin-5-amine;3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-isopropylpyrazolo[1,5-α]pyridin-5-amine;N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-pyrazolo[1,5-α]pyridin-5-amine;and3-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-isopropyl-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine;4-Bromo-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine;4-Chloro-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine;4-Bromo-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine;4-Chloro-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine;4-{5-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-α]pyridin-2-yl}phenol;N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-isobutoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine;andN-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[4-(cyclopropylmethoxy)phenyl]pyrazolo[1,5-α]pyridin-5-amine,and pharmaceutically acceptable salts thereof.
 16. A pharmaceuticalcomposition comprising a compound according to claim
 1. 17. Thepharmaceutical composition according to claim 16 further comprising apharmaceutically acceptable carrier or diluent.
 18. The pharmaceuticalcomposition according to claim 16 further comprising an antiviral agentselected from the group consisting of aciclovir and valaciclovir.
 19. Amethod for the treatment of a herpes viral infection selected from HSV-1and HSV-2 in an animal, said method comprising administering to theanimal a therapeutically effective amount of a compound according toclaim
 1. 20. A method for treatment of a condition or disease associatedwith a herpes viral infection selected from HSV-1 and HSV-2 in ananimal, comprising administering to the animal a therapeuticallyeffective amount of the compound of formula (I) according to claim 1.21. A process for preparing a compound according to claim 1 wherein R²is selected from the group consisting of alkyl, cycloalkyl, alkenyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het —S(O)_(n)R⁹,—S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het,—NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; and R³ and R⁴ are H, said processcomprising reacting a compound of formula (IX):

wherein at least one R⁶ is selected from the group consisting of —NR⁷R⁸,—NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; with an amine of formula (X):


22. A process for preparing a compound according to claim 1, saidprocess comprising the steps of: (a) reacting the compound of formula(XXXII)

wherein p′ is 0, 1 or 2; with diphenylphosphoryl azide in tert-butanolto give the compound of formula (I-X)

(b) optionally cleaving the compound of formula (I-X) to give thecompound of formula (I-Y)

and (c) optionally converting the compound of formula (I-Y) to acompound of formula (I-Z)

wherein R^(6x) is selected from the group consisting of —NR⁷R⁸ where R⁷and R⁸ are not both H, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; usingconditions selected from the group consisting of cross coupling,reductive amination, alkylation, acylation and sulfonylation.
 23. Aprocess for preparing a compound according to claim 1 wherein R² isselected from the group consisting of alkyl, cycloalkyl, alkenyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het —S(O)_(n)R⁹,—S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het,—NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; R³ is selected from the groupconsisting of H, alkyl, cycloalkyl, alkenyl, Ay, Het, —C(O)R⁷, —C(O)Ay,—CO₂R⁷, —CO₂Ay, —SO₂NHR⁹, —NR⁷R⁸ (where R⁷ and R⁸ are not H), —NR⁷Ay(where R⁷ is not H), —R¹⁰⁰R⁷, —R¹⁰OAy, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; R⁴ is H;and at least one R⁶ is selected from the group consisting of—NR⁷R⁸,—NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het, said process comprising thesteps of: a) reacting a compound of formula (XVI):

wherein each R⁶ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het,—C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay,—C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay,—NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰Ay,—R¹⁰Het, —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹, —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het,—R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,—R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹,—R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or twoadjacent R⁶ groups together with the atoms to which they are bonded forma C₅₋₆ cycloalkyl or a 5- or 6-membered heterocyclic group containing 1or 2 heteroatoms; wherein at least one R⁶ is selected from the groupconsisting of halo, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; withan amine of formula (X):

to prepare a compound of formula (XVII):

wherein at least one R⁶ is selected from the group consisting of halo,—NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; and b) in the embodimentwherein no R⁶ is —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay or —NHR¹⁰Het,replacing R⁶ halo of the compound of formula (XVII) with an aminesubstituent selected from the group consisting of—NR⁷R⁸, —NR⁷Ay, —NHHet,—NHR¹⁰Ay and-NHR¹⁰Het; to prepare a compound of formula (I).
 24. Aprocess for preparing a compound according to claim 1 wherein R² isselected from the group consisting of alkyl, cycloalkyl, alkenyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het —S(O)_(n)R⁹,—S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Het,—NHR¹⁰Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; and at least one R⁶ is selected fromthe group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het,said process comprising the steps of: a) reacting a compound of formula(XX):

wherein each R⁶ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het,—C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay,—C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay,—NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰Ay,—R¹⁰Het, —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹, —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het,—R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,—R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹,—R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or twoadjacent R⁶ groups together with the atoms to which they are bonded forma C₅₋₆cycloalkyl or a 5- or 6-membered heterocyclic group containing 1or 2 heteroatoms; wherein at least one R⁶ is selected from the groupconsisting of halo, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; withan amine of formula (X):

to prepare an intermediate compound; b) oxidizing the intermediatecompound to prepare a compound of formula (XVII):

wherein at least one R⁶ is selected from the group consisting of halo,—NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; and c) in the embodimentwherein no R⁶ is —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay or —NHR¹⁰Het,replacing R⁶ halo of the compound of formula (XVII) with an aminesubstituent selected from the group consisting of —NR⁷R⁸, —NR⁷Ay,—NHHet, —NHR¹⁰Ay and—NHR¹⁰Het; to prepare a compound of formula (I). 25.A process for preparing a compound according to claim 1 wherein at leastone R⁶ is selected from the group consisting of —NR⁷R⁸, —NR⁷Ay, —NHHet,—NHR¹⁰Ay and —NHR¹⁰Het, said process comprising the steps of: a)reacting a compound of formula (XXII):

wherein each R⁶ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het,—C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay,—C(O)Het, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay,—NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, —NHHet, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰Ay,—R¹⁰Het, —R¹⁰OR⁹, —R¹⁰—O—C(O)R⁹, —R¹⁰—O—C(O)Ay, —R¹⁰—O—C(O)Het,—R¹⁰—O—S(O)_(n)R⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,—R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹,—R¹⁰SO₂R⁹, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, cyano, nitro and azido; or twoadjacent R⁶ groups together with the atoms to which they are bonded forma C₅₋₆cycloalkyl or a 5- or 6-membered heterocyclic group containing 1or 2 heteroatoms; wherein at least one R⁶ is selected from the groupconsisting of halo, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; andX¹ is chloro, bromo or iodo; with a compound of formula (XXIV):

wherein M² is selected from the group consisting of —B(OH)₂, —B(ORa)₂,—B(Ra)₂, —Sn(Ra)₃, Zn-halide, ZnRa, and Mg-halide where Ra is alkyl orcycloalkyl and halide is halo; to prepare a compound of formula (XVII):

wherein at least one R⁶ is selected from the group consisting of halo,—NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het; and b) in the embodimentwherein no R⁶ is —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay or —NHR¹⁰Het,replacing R⁶ halo of the compound of formula (XVII) with an aminesubstituent selected from the group consisting of —NR⁷R⁸, —NR⁷Ay,—NHHet, —NHR¹⁰Ay and—NHR¹⁰Het; to prepare a compound of formula (I).